A Bitter Taste in Your Heart

Abstract

The human genome contains ∼29 bitter taste receptors (T2Rs), which are responsible for detecting thousands of bitter ligands, including toxic and aversive compounds. This sentinel function varies between individuals and is underpinned by naturally occurring T2R polymorphisms, which have also been associated with disease. Recent studies have reported the expression of T2Rs and their downstream signaling components within non-gustatory tissues, including the heart. Though the precise role of T2Rs in the heart remains unclear, evidence points toward a role in cardiac contractility and overall vascular tone. In this review, we summarize the extra-oral expression of T2Rs, focusing on evidence for expression in heart; we speculate on the range of potential ligands that may activate them; we define the possible signaling pathways they activate; and we argue that their discovery in heart predicts an, as yet, unappreciated cardiac physiology.

Extra-Oral Expression of Bitter T2Rs

TAS2R/T2Rs (gene and protein) were first discovered within type II taste receptor cells in the tongue and act as sentinels in protecting against the ingestion of potentially toxic substances (Chandrashekar et al., 2000; Lu et al., 2017). Since these pioneering studies, T2R expression has been reported in a multitude of extra-oral tissues, including the gut, lungs, brain, and heart (Shah et al., 2009; Foster et al., 2013; Garcia-Esparcia et al., 2013), but their complete function(s) in physiology and pathophysiology remain to be defined. In Table 1, we have summarized the location, expression profile and proposed function for the T2R family across a range of human tissues and cells. In regard to function, we would offer a note of caution that a number of studies (listed in Table 1) have proposed functions based on stimulation with various bitter compounds in the micromolar to millimolar range where the selectivity and specificity toward T2Rs may reasonably be questioned. Despite this, the expression of T2Rs within the cardiovascular system, particularly the heart and vasculature, has gained significant interest in recent years. Following our initial discovery of TAS2Rs within the heart (Foster et al., 2013), a number of subsequent studies have focused on the vasculature (Lund et al., 2013; Manson et al., 2014; Upadhyaya et al., 2014; Chen et al., 2017). An unambiguous definition of their function has, however, lagged behind the capacity to demonstrate their expression.

The expression of TAS2Rs in different tissues and cell lines has been examined using RT-PCR, qPCR, microarray techniques as well as RNAseq (Flegel et al., 2013). Most recently, Jaggupilli et al. (2017) used nCounter gene expression analysis to characterize the expression of the 29 human TAS2Rs in a variety of cell lines (Table 1). Their results showed that TAS2R14 and TAS2R20 were highly expressed; TAS2R3, −4, −5, −10, −13, −19, and −50 were moderately expressed; TAS2R8, −9, −21 and −60 had low level of expression; and TAS2R7, −16, −38, −39, −40, −41, and −42 were barely detectable. The nCounter technique relies on hybridization of complementary probes (spanning 100 nucleotide bases) for each gene, and hence, TAS2R30, −31, −43, −45, and −46 could not be accurately discerned from one another, as they share >92% homology. Nevertheless, this data clearly shows that some T2Rs are broadly and differentially expressed, whereas others are more restricted in their tissue distribution.

Model Systems for Expressing T2Rs and Defining Their Function

In attempting to define the function of, and to identify ligands for, the T2Rs, researchers have established heterologous expression systems in human cells (e.g., HEK293 or HEK293T) (Meyerhof et al., 2010). However, the use of these cells for understanding the underlying mechanisms and signaling pathways within cardiovascular tissues/cells has obvious limitations. Firstly, due to the insufficient cell surface targeting of T2Rs in heterologous cells (Chandrashekar et al., 2000), chimeric T2Rs encompassing the amino terminus of the rat somatostatin receptor subtype 3 are often used to improve expression and functionality (Bufe et al., 2002; Behrens et al., 2006). Furthermore, a chimeric G protein consisting of the Gα₁₆ and 44 amino acids of gustducin attached to the carboxyl terminus is widely used in calcium mobilization assays (Liu et al., 2003; Ueda et al., 2003). Gα₁₆ has been coined the ‘universal adaptor’ due to its ability to interact with numerous GPCRs and provides a robust readout for receptor activation, including for T2Rs (Ueda et al., 2003). While these artificial heterologous systems have proven useful in identifying ligands for orphan receptors (Meyerhof et al., 2010) and interrogating the structure-function aspects of T2Rs (Brockhoff et al., 2010), the field is now moving toward more relevant cellular models with endogenous receptors and signaling partners (Freund et al., 2018).

Studies using the aforementioned heterologous expression system have demonstrated that the majority of T2Rs form oligomers, both homodimers and heterodimers (Kuhn et al., 2010). However, unlike the situation for umami/sweet taste sensation (requiring dimerization of T1R1/T1R2 and T1R1/T1R3), T2R homodimers did not appear to alter the pharmacology of the receptors, nor do they have obvious influence on protein expression or membrane localization (Kuhn et al., 2010). In contrast, Kim et al. (2016) used immuno-fluorescent microscopy to show that the co-expression of the adrenergic (ADRβ₂) receptor with T2R14 resulted in a ∼3-fold increase in cell-surface expression of T2R14. Co-immunoprecipitation and biomolecular fluorescence complementation experiments confirmed that the increase of cell-surface expression was attributed to the formation of T2R14:ADRβ₂ heterodimers. These complexes may be particularly important in heart where the actions of adrenergic receptors are well described. Interestingly, co-immunoprecipitation and co-internalization of ADRβ₂:M71 OR (mouse 71 olfactory receptor) was observed in response to their specific ligands (Hague et al., 2004). These seminal observations in heterologous systems need to be confirmed and extended with endogenous models to clarify our understanding of how T2Rs function in vivo and to define their potential modulation of (or by) established GPCRs.

Another important issue in considering model expression systems for studying T2Rs is the requirement for appropriate accessory proteins and correct post-translational processing. It is now well-established that chemosensory receptors [e.g., odorant (McClintock et al., 1997) and pheromone (Loconto et al., 2003) receptors] rely on endogenous proteins in order to be targeted to the cell-surface. A study by Behrens et al. (2006) demonstrated that certain members of the receptor-transporting protein (RTP) and receptor expression enhancing protein (REEP) families enhance cell-surface localization and functionality of certain TAS2Rs, likely through protein–protein interactions. Furthermore, it was shown that varying combinations of these proteins are expressed endogenously within tissues (circumvallate papillae and testis) that express TAS2R genes. Interestingly, the human heart differentially expresses REEP 1, 2, 3, 5, and 6 across heart regions (Doll et al., 2017), suggesting that efficient cell-surface TAS2R expression may also be region specific. Nonetheless, these trafficking proteins do not universally promote T2R functionality, for instance T2R14 showed no increase in capacity to mobilize calcium when co-expressed with either RTP or REEP (Behrens et al., 2006). There is accumulating evidence that the degree of T2R membrane insertion is dependent on the specific tissue. As T2Rs are detected in a myriad of tissues, multiple endogenous mechanisms may contribute to their appropriate expression and localization. As for many GPCRs, N-glycosylation of T2Rs is important for cell-surface localization–Reichling et al. (2008) reported that glycosylation of the second extracellular loop is essential for the recruitment (via association with the cellular chaperone calnexin) and insertion of TAS2Rs in the cell membrane; moreover, the function of non-glycosylated TAS2R16 could be rescued when co-expressed with RTP3 and RTP4.

The Cardiac Gpcr Repertoire Includes T2Rs

The human heart expresses over 200 different GPCRs (Wang et al., 2018), some of which are critical for regulating cardiac morphology and function (Capote et al., 2015). Intriguingly, the gene transcripts for more than half of the TAS2R family were detected in both left ventricle and right atria (Foster et al., 2013) ranging in abundance between that observed for two classically important cardiac GPCRs – the angiotensin II type 1 receptor and β₁-adrenergic receptor (ADRβ₁). It is notable that the expression of TAS2R14 was equivalent to that of ADRβ₁ in the left ventricle. These findings are supported by publicly available Illumina Human BodyMap 2.0 project RNA-seq dataset (Flegel et al., 2013), which showed widespread TAS2R expression in human tissues and highest expression of TAS2R14 in heart. It is important, however, to note that T2Rs are not uniformly detected by all techniques, with TAS2R9, TAS2R39, and TAS2R45 not detected in the Illumina RNA-seq data set, but detected by qPCR (Foster et al., 2013). These differences could reflect individual variations, noting the body map is from one patient or the more specific nature of RNA-seq over qPCR. Interestingly, the expression of TAS2Rs are differentially regulated with age in mice (Foster et al., 2013), but not with sex or in heart failure (Foster et al., 2015a). Furthermore, analysis of the publicly available GTEx LDACC and BioGPS Human Cell Type and Tissue Gene Expression Profiles RNA-seq datasets, highlight the expression of GNAT3 (the taste receptor specific G protein, Gα_Gustducin) in a variety of human tissues, including the heart.

We previously investigated the factors contributing to cardiac TAS2R gene expression in silico (Foster et al., 2015a). Similar to rodent Tas2rs, there was no evidence of enrichment for particular transcription factor binding sites in the proximal promoter regions of the human TAS2R genes. However, we observed thatTAS2R14 (the most abundantly expressed) had the strongest evidence of regulatory activity in its promoter region, i.e., active methylation marks overlapping with the DNase I hypersensitivity cluster. On this basis, although we cannot rule out the presence of specific transcription factors that regulate TAS2R gene expression, we reason that the proximal regulatory regions for some, but not all, TAS2R genes might show a basal level of transcriptional activity. This, combined with their multigene cluster expression profiles could facilitate preferential transcription of the specific TAS2Rs (Foster et al., 2015a).

The heart is made up of 2–3 billion cardiomyocytes and yet these cells constitute less than a third of all heart tissue (Tirziu et al., 2010). The remaining, more than two thirds of the heart consists of smooth muscle, fibroblasts, other connective tissue cells, endothelial cells, sinoatrial cells, atrioventricular cells, Purkinje cells, pluripotent cardiac stem cells, mast cells, and other immune system-related cells (Tirziu et al., 2010). We have demonstrated that certain Tas2rs (rodent) were expressed within both cardiomyocytes and fibroblasts, as well as their downstream signaling effectors (Gnat3, Plcβ2, Trpm5) (Foster et al., 2013). These data suggest that specific cells within the heart may express varying populations of TAS2R, similar to that seen in other systems (Table 1). As technology advances, including single cell sequencing and proteomics (Uhlen et al., 2015), the topography of T2Rs within the heart will provide insight into how these receptors function within this system.

Signaling and Function of T2Rs Within the Cardiovascular System

The binding of bitter ligands to T2Rs results in a conformation change in the receptor allowing it to interact with Gα_Gustducin and Gβ_1/3γ₁₃ (Huang et al., 1999), which then activate subsequent downstream pathways (Yan et al., 2001). Knockout (KO) studies have provided conclusive evidence supporting these signaling pathways. Mice lacking either PLCβ2 or TRPM5 exhibited diminished or ablated taste responses to bitter compounds (Zhang et al., 2003). Furthermore, Gα_Gustducin KO mice had increased levels of cAMP, compared to the wild-type mice as well as displaying severely impaired responses to the tested compounds (Clapp et al., 2008). As with Gαi-family G proteins, Gα_Gustducin can decrease the levels of cAMP, via the activation of phosphodiesterases, which has been observed in response to two bitter compounds, denatonium and strychnine (Yan et al., 2001). Finally, mice that were genetically modified to express novel human T2Rs demonstrated a strong aversive response to ligands that was not evident in wild-type mice (Mueller et al., 2005).

With the discovery of TAS2R expression in cardiac tissue (Foster et al., 2013), defining the signaling transduction pathway is of particular interest, yet there is limited evidence for the presence of all the classical taste signaling components in heart. The expression of Gα_Gustducin has been shown in human heart tissue, and is particularly enriched in cardiomyocytes (BioGPS Human Cell Type and Tissue Gene Expression Profiles RNA-seq datasets). However, studies have not observed Gγ₁₃ (Huang et al., 1999) or TRPM5 (Demir et al., 2014). TRPM4 is present within human heart tissues (Guinamard et al., 2004; Demir et al., 2014), however, both TRPM4 and TRMP5 are considered necessary for taste signal transduction (Dutta Banik et al., 2018). Hence, alternative signal transduction pathways that could mediate the effects of taste receptors in the cardiovascular system should be considered.

A study by Ueda et al. (2003) demonstrated that T2R16 could couple to a chimeric G protein consisting of the N-terminus of Gα₁₆ and the last 44 amino acids of either Gα_Gustducin, Gα_t2or Gα_i2. Furthermore, the expression of all three of these Gα subunits have been identified in taste receptor cells, with the frequency of Gα_i2 being higher than that of Gα_Gustducin (Ueda et al., 2003). Figure 1 shows a comparison of Gα_Gustducin and Gα_i2, highlighting the highly conserved amino acid residues and the region known to interact with TAS2Rs. Substitution of glycine³⁵² for proline in Gα_Gustducin disrupts T2R interaction with Gα_Gustducin, although its coupling to the Gβγ and effector molecules was preserved (Ruiz-Avila et al., 2001). This suggests that the extreme C terminus of both Gα_Gustducin and Gα_i2 are capable of, and necessary for T2R:G protein coupling and transduction. Importantly, in human airway smooth muscle (HASM), the reported expression of Gα_i2 expression was 100-fold higher than that of Gα_Gustducin and T2R14 was shown to couple to all Gα_i proteins, particularly Gα_i2 (Kim et al., 2017). The use of pertussis toxin was able to abrogate the T2R mediated relaxation in HASM (Kim et al., 2017), consistent with previous studies, where T2Rs has been shown to couple with inhibitory signaling pathways (Ozeck et al., 2004). The actions of T2R may also include other inhibitory type processes, such as described by Zhang et al. (2013) in airway smooth muscle cells (Lu et al., 2017). Taken together these observations suggest that depending on the level of G protein expression and the strength of the subsequent signal, T2Rs likely couple and signal in a cell/tissue specific manner, which may include (or not) Gα_Gustducin.

FIGURE 1

Indeed, T2R signaling within cardiac cells might reasonably reflect those described for the respiratory system and vascular systems (summarized in Figure 2). The heart is known to express specific varying combinations of Gα (including Gα_i2), Gβγ and various signaling effector molecules (Doll et al., 2017). In a series of experiments in Langendorff-perfused mouse hearts, we observed dose-dependent negative inotropic effects in response to bitter ligands (Foster et al., 2014). A ∼40% decrease in left ventricular developed pressure and an increase in aortic pressure in response to sodium thiocynate were shown to be Gα_i-dependent. Some alterations in cardiovascular physiology were not attributed to G proteins (not blocked by pertussis toxin and gallein), however, it was shown that rodents express GNAT3 (Gα_Gustducin) in their cardiomyocytes (Foster et al., 2013). This further supports the premise that T2Rs can signal through various G proteins. While there is no clear consensus on the precise mechanism, there is an agreement that bitter ligands mediate contractile responses in the vasculature. One study demonstrated a transient drop in blood pressure upon intravenous injection of denatonium benzoate into rats (Lund et al., 2013). Additionally, Manson et al. (2014) attributed the endothelium-independent relaxation of precontracted human pulmonary arteries to the application of bitter ligands for T2Rs (3, 4, 10, and 14). In contrast, denatonium benzoate has been shown to enhance the tone of endothelium-denuded rat aorta rings, which was attributed to specific Tas2r activation (Tas2r40, 108, 126, 135, 137, 143) via Gα_Gustducin (Liu et al., 2020). Whether the actions of T2Rs in cardiomyocytes have a direct effect on the force and strength of contraction of individual myocytes remains to be determined. Equally, there is a possibility that these receptors may be expressed in other cell populations, including the specific cells of the conduction system (SA node, AV node, Purkinje Fibers).

FIGURE 2

Naturally Occurring Polymorphisms and Disease

GPCRs and their respective ligands have profound homeostatic and regulatory effects on the cardiovascular system. Not surprisingly, mutations and modifications of cardiovascular GPCRs, G proteins and their regulatory proteins are linked to dysfunction and disease (Foster et al., 2015b). T2Rs are one of the most heterogenous and unique families of GPCRs and are now considered as a separate group of receptors (Di Pizio and Niv, 2015). According to the HGNC database, there are 39 genetically diverse and highly polymorphic TAS2R single exon genes that encode for 29 functional T2Rs (and 10 non-coding pseudogenes) in humans (Devillier et al., 2015). This is in contrast to the majority of literature that cite the existence of only 25 functional T2Rs (Meyerhof et al., 2010; Lossow et al., 2016). On average, TAS2R genes contain four single nucleotide polymorphisms (SNPs) of which the vast majority are non-synonyms mutations that encode amino acid substitutions (Kim et al., 2005). Table 2 outlines all of the non-synonymous SNPs present within the population and their penetrance. These TAS2R genes are located on chromosomes 5, 7, and 12 (Adler et al., 2000; Foster et al., 2015a), with dense clustering on chromosomes 7 and 12. The close proximity is thought to underpin the enormous variation and diversification of the T2R repertoire within humans.

The importance of uncovering the primary function of T2Rs in the heart is supported by the critical role they play within the respiratory system. TAS2R38 is expressed in all aspects of the upper and lower respiratory tracts including sinonasal epithelial cells, bronchial epithelial cells, bronchial smooth muscle, and pulmonary vasculature smooth muscle (Shah et al., 2009; Grassin-Delyle et al., 2013; Upadhyaya et al., 2014; Devillier et al., 2015). Application of phenylthiocarbamide (PTC) or two quorum sensing molecules (C4HSL and C12HSL) secreted by Pseudomonas aeruginosa were shown to increase mucociliary clearance, bronchodilation, and production of bactericidal levels nitric oxide in explanted human tissue samples and primary airway–liquid interface cultures (Lee et al., 2012). This supports the recent finding that T2Rs play a role in innate immunity, as quorum sensing molecules serve to communicate between bacterial populations, allowing them to establish themselves during infection (Lee et al., 2014). Bitter taste receptors, particularly TAS2R38, are a unique and diverse family of GPCRs due to the number of their naturally occurring genetic variants (Kim et al., 2005). Compared to the functional (PAV) haplotype, individuals with the non-functional (AVI) haplotype were shown to be more susceptible to respiratory infections as the receptor was unable to detect the compounds and respond appropriately (Lee et al., 2012). A similar result was seen with regard to oral innate immunity (Gil et al., 2015). TAS2R38 PAV/PAV mRNA was upregulated ∼4.3-fold in response to Streptococcus mutans bacteria (over the unstimulated control) whereas the AVI/AVI was only ∼1.2-fold. Furthermore, the level of hBD-2 (antimicrobial peptide) induced was highest in those with the PAV/PAV genotype (Gil et al., 2015). On this basis, the authors concluded that a person’s T2R38 genotype determines oral innate immunity.

Natural polymorphisms are no longer thought only to account for differences in oral bitter taste perception (Roudnitzky et al., 2016). It is now recognized that these polymorphisms also influence other important aspects of our physiology including alcohol dependence, eating behavior, longevity, glucose homeostasis and regulation of thyroid hormones (Dotson, 2008; Hayes et al., 2011; Campa et al., 2012; Clark et al., 2015). There are 132 naturally occurring non-synonymous polymorphisms for cardiac-expressed T2Rs and it is clear that the majority of these remain uncharacterized (Table 3). One polymorphism that is of particular interest is T2R50-rs1376251, as debate remains in the literature over its potential association with myocardial infarction and coronary heart disease (Shiffman et al., 2008; Tepper et al., 2008; Yan et al., 2009; Koch et al., 2011; Ivanova et al., 2017; Tsygankova et al., 2017). There are also polymorphisms outside of the taste receptor coding region, or those that result in synonymous mutations that have been associated with changes in physiology. Of note, T2R14 rs3741843 has been associated with decreased sperm motility (Gentiluomo et al., 2017). Individuals that were homozygous carriers for the (G) allele, encoding arginine (R – AGG), showed a decreased sperm progressive motility compared to heterozygotes and homozygotes for the (A) allele, which encodes arginine (R – AGA). The authors rationalized using in silico analysis that T2R14 regulates the expression of T2R43. Furthermore, an upstream mutation of TAS2R3 rs11763979 can regulate the expression of WEE2 antisense RNA one (WEE2-AS1), which increases the expression of WEE2 within the testis. WEE2 is a protein tyrosine kinase involved in the regulation of cell cycle progression (Nakanishi et al., 2000). Overexpression of WEE2 in the testis was hypothesized to increase the number of abnormal sperm cells (Gentiluomo et al., 2017). Despite recent progress, it is unclear the full extent to which polymorphisms can influence T2R physiology, although it is clear investigation into their effects is warranted.

Potential Cardiovascular T2R Ligands

T2Rs are unique as they lack most of the conserved motifs of the class A GPCR family (Lagerstrom and Schioth, 2008). The intracellular loops – regions necessary for signal transduction and feedback modulation (Moreira, 2014), were shown to be more conserved across T2Rs than the extracellular loops that are generally implicated in receptor binding (Meyerhof, 2005). Using T2R14 as an example, Nowak et al. (2018) demonstrated that in vitro mutagenesis of 19 receptor mutants (all within the binding pocket) retained the ability to bind at least one of the 7 tested agonists while some improved signaling compared to the wild type. These results are consistent with previous literature that ligands bind within the transmembrane and extracellular domain regions (Brockhoff et al., 2010; Upadhyaya et al., 2015). Interestingly, of the highly expressed cardiac T2Rs, T2R10, T2R14, and T2R46 were shown to bind a wide array of ligands, which is considered disproportional in comparison to the others (Meyerhof et al., 2010). Over 75% of the list of ligands in Table 3 were shown to activate these three broadly tuned T2Rs.

Universally, researchers have used chemicals that ‘taste bitter’ to test for potential ligands. However, if heart tissue expresses over half of the T2Rs family, a major question arises - what is the source of ligands for these T2Rs within the cardiovascular system? We would argue there are four major sources: (1) bitter compounds in food, (2) endogenously produced factors, (3) bacterial metabolic by-products and toxins and (4) chemicals/drugs (outlined in Table 3).

The post-prandial concentration of bitter compounds in the blood increases. One perhaps common example of this is caffeine, which reportedly modulates calcium signaling via interaction with the ryanodine receptor (Kong et al., 2008). Interestingly, caffeine also activates T2R10, -14, and -46 (Meyerhof et al., 2010; Cappelletti et al., 2018) at concentrations that occur in blood post-prandially and which are equivalent to levels that modulate the ryanodine receptor (Kong et al., 2008). In the gut, caffeine activation of T2R has been linked to gastric secretion (Liszt et al., 2017). Caffeine may also act as a stimulate for the central nervous system via the antagonism of adenosine receptors (Fisone et al., 2004). Hence in considering the homeostatic consequence of bitter compounds (such as caffeine) one must also accept that at high concentrations they are interacting with multiple receptor systems. We would anticipate that many bitter compounds in food would have actions on both T2Rs and other targets.

Another interesting possibility is that the body produces endogenous factors that could activate T2Rs. Currently, alanine, pantothenic acid (vitamin B5), steroids (androsterone and progesterone) and taurocholic acid (primary bile acid) have all been identified as ligands for specific receptors (Ji et al., 2014; Lossow et al., 2016). Potentially, the cardiotonic steroids may be ligands for cardiac-expressed T2Rs, although ouabain has already been shown not to be an agonist in vitro (Meyerhof et al., 2010), despite being able to augment calcium transients in arterial smooth muscle (Arnon et al., 2000). The other members of this family could also be investigated as potential ligands for cardiac T2Rs. Whether hormones/factors produced by other tissues, or indeed paracrine factors released from cardiac cells, can bind and activate cardiac T2Rs remains to be determined, but is an area of intense interest.

A more provocative idea is that colonizing bacteria, in complex organisms, could produce bitter compounds, including metabolic by-products and other signaling molecules that alter our physiology via T2Rs. A recent study showed commensal bacteria are enable to synthesize GPCR ligands that mimic human signaling molecules (Cohen et al., 2017). Broad screening for bacterial metabolites that activate GPCRs (Chen et al., 2019; Colosimo et al., 2019) have identified numerous candidates, but unfortunately these screens have not included the taste receptors. Interestingly, an olfactory receptor (Olfr78) has been reported to respond to short chain fatty acids produced by gut bacteria (Pluznick et al., 2013). Olfr78 KO mice had elevated blood pressure when treated with antibiotics. As for the T2Rs, T2R38 although its expression is low in the heart, was shown to be broadly tuned for seven bacterial metabolites (Verbeurgt et al., 2017). It is also worth noting that during infections bacterial toxins could be ‘bitter’ and interact with T2Rs once they reached a certain concentration in the blood. One example is quorum sensing molecules - when they reach a certain concentration, bacteria produce a biofilm in order to evade and survive the host immune defense system (Davies et al., 1998). Therefore, it is plausible that T2Rs may alter cardiovascular physiology in response to systemic infections such as sepsis where dramatic cardiovascular changes are observed, e.g., decreased myocardial contractility, vasodilation, endothelial injury and increased heart rate (Singer et al., 2016).

Finally, it is important to address the possibility that off-target activation of T2Rs may play a role beyond normal physiology and mediate unexpected responses to therapeutic drugs, many of which are bitter. Indeed, the possibility that T2Rs act as the mediators of off-target drug effects due to the prevalence of their expression throughout the body has been discussed previously (Clark et al., 2012). There are numerous drugs/chemicals that have specific, detrimental cardiovascular effects and, moreover, these chemicals have been shown to activate specific T2Rs at concentrations to those that elicit these adverse effects.

Future Directions

The continuous, proper functioning of the heart is fundamental to life. The discovery of T2Rs expressed in cardiac cells predicts important (but yet to be appreciated) roles in heart physiology, as well as its response to external challenges (e.g., diet, metabolic changes, infections, and drugs). Research and knowledge regarding the physiology of T2Rs within the human heart is challenging, primarily due to the constraints of readily acquiring suitable human heart tissue samples. Furthermore, the lack of homology between rodent Tas2rs and human T2Rs (Foster et al., 2013), limits the utility of gene modified animal models to directly inform human physiology. Additionally, the 29 T2Rs (and their many variants) have been historically difficult to heterologously express on the cell membrane of model cells, and this has impeded further investigation of their signaling properties.

It is important to note, that researchers have ectopically expressed human T2Rs in mice and this has provided strong confirmation that a given ligand (tastants) can activate a specific human T2R (Mueller et al., 2005). Perhaps future experiments might extend this approach to develop transgenic mice expressing human T2Rs in a cell-specific context. Stimulation of these receptors with ligands that selectively bind and activate only human T2Rs could provide important insights into the physiological role(s) of T2Rs in human tissues.

Another critical objective will be to develop appropriate cardiac models that express endogenous receptors and recapitulate cardiac physiology. One major advance in cardiovascular research has been the development of induced pluripotent stem cell-derived human cardiomyocytes (Hudson et al., 2012; Soong et al., 2012) and human cardiac organoids (Nugraha et al., 2019). These models will offer the unique opportunity to modulate T2R expression in cardiomyocytes and to thereby investigate bitter ligand-driven changes in cardiac gene transcription, as well as to define alterations in cardiac contractility and function.

Finally, the ultimate goal will be to attribute T2R-mediated expression, activation and signaling to definitive changes in human cardiovascular function in vivo. In order for this to succeed, the following challenges need to be resolved - the promiscuity of bitter receptor–ligand interactions, the elucidation of tissue-specific T2R signaling, as well as the lack of definitive research tools (e.g., selective antibodies to T2Rs and specific receptor antagonists). We anticipate that studies focused on examining the functionality (or lack thereof) for the various highly penetrant, cardiac-expressed T2R polymorphisms may provide the means for unambiguously attributing T2R activation to a specific physiological outcome. Analogous to the advances made with non-functional T2R38 variants (T2R38AVI) in the lung, we predict that non-functional, cardiac-expressed T2Rs can be identified and these will prove to be critical in providing the necessary controls for investigating explanted cardiac tissues.

References

• 1

  AbernathyA.AlsinaL.GreerJ.EgermanR. (2017). Transient fetal tachycardia after intravenous diphenhydramine administration.Obstet. Gynecol.130374–376. 10.1097/AOG.0000000000002147

  • CrossRef
  • Google Scholar

• 2

  AdamsH. R.ParkerJ. L.MathewB. P. (1979). Cardiovascular manifestations of acute antibiotic toxicity during E coli endotoxin shock in anesthetized dogs.Circ. Shock6391–404.

  • Google Scholar

• 3

  AdlerE.HoonM. A.MuellerK. L.ChandrashekarJ.RybaN. J.ZukerC. S. (2000). A novel family of mammalian taste receptors.Cell100693–702. 10.1016/s0092-8674(00)80705-9

  • CrossRef
  • Google Scholar

• 4

  AnsoleagaB.Garcia-EsparciaP.PinachoR.HaroJ. M.RamosB.FerrerI. (2015). Decrease in olfactory and taste receptor expression in the dorsolateral prefrontal cortex in chronic schizophrenia.J. Psychiatr. Res.60109–116. 10.1016/j.jpsychires.2014.09.012

  • CrossRef
  • Google Scholar

• 5

  ArnonA.HamlynJ. M.BlausteinM. P. (2000). Ouabain augments Ca(2+) transients in arterial smooth muscle without raising cytosolic Na(+).Am. J. Physiol. Heart Circ. Physiol.279H679–H691. 10.1152/ajpheart.2000.279.2.H679

  • CrossRef
  • Google Scholar

• 6

  BarbagalloM.DominguezL. J.LicataG.ShanJ.BingL.KarpinskiE.et al (2001). Vascular effects of progesterone : role of cellular calcium regulation.Hypertension37142–147. 10.1161/01.hyp.37.1.142

  • CrossRef
  • Google Scholar

• 7

  BarberM.NguyenL. S.WassermannJ.SpanoJ. P.Funck-BrentanoC.SalemJ. E. (2019). Cardiac arrhythmia considerations of hormone cancer therapies.Cardiovasc. Res.115878–894. 10.1093/cvr/cvz020

  • CrossRef
  • Google Scholar

• 8

  BarhamH. P.CooperS. E.AndersonC. B.TizzanoM.KingdomT. T.FingerT. E.et al (2013). Solitary chemosensory cells and bitter taste receptor signaling in human sinonasal mucosa.Int. Forum. Allergy Rhinol.3450–457. 10.1002/alr.21149

  • CrossRef
  • Google Scholar

• 9

  BasyigitI.KahramanG.IlgazliA.YildizF.BoyaciH. (2005). The effects of levofloxacin on ECG parameters and late potentials.Am. .J Ther.12407–410. 10.1097/01.mjt.0000127358.38755.c5

  • CrossRef
  • Google Scholar

• 10

  BehrensM.BarteltJ.ReichlingC.WinnigM.KuhnC.MeyerhofW. (2006). Members of RTP and REEP gene families influence functional bitter taste receptor expression.J. Biol. Chem.28120650–20659. 10.1074/jbc.M513637200

  • CrossRef
  • Google Scholar

• 11

  BiancanielloT.MeyerR. A.KaplanS. (1981). Chloramphenicol and cardiotoxicity.J. Pediatr.98828–830.

  • Google Scholar

• 12

  BrockhoffA.BehrensM.NivM. Y.MeyerhofW. (2010). Structural requirements of bitter taste receptor activation.Proc. Natl. Acad. Sci. U.S.A.10711110–11115. 10.1021/jf403387p

  • CrossRef
  • Google Scholar

• 13

  BrownA. L.LaneJ.CoverlyJ.StocksJ.JacksonS.StephenA.et al (2009). Effects of dietary supplementation with the green tea polyphenol epigallocatechin-3-gallate on insulin resistance and associated metabolic risk factors: randomized controlled trial.Br. J. Nutr.101886–894. 10.1017/S0007114508047727

  • CrossRef
  • Google Scholar

• 14

  BrownG.BoldtC.WebbJ. G.HalperinL. (1997). Azathioprine-induced multisystem organ failure and cardiogenic shock.Pharmacotherapy17815–818.

  • Google Scholar

• 15

  BufeB.HofmannT.KrautwurstD.RaguseJ.-D.MeyerhofW. (2002). The human TAS2R16 receptor mediates bitter taste in response to β-glucopyranosides.Nat. Genet.32397–401. 10.1038/ng1014

  • CrossRef
  • Google Scholar

• 16

  BustamanteD.MoralesM.PelissierT.SaavedraH.MirandaH. F.PaeileC. (1989). Experimental cardio-depressant effects of clonixin.Gen. Pharmacol.20605–608. 10.1016/0306-3623(89)90094-3

  • CrossRef
  • Google Scholar

• 17

  CampaD.De RangoF.CarraiM.CroccoP.MontesantoA.CanzianF.et al (2012). Bitter taste receptor polymorphisms and human aging.PLoS One7:e45232. 10.1371/journal.pone.0045232

  • CrossRef
  • Google Scholar

• 18

  CampbellM. C.RanciaroA.ZinshteynD.Rawlings-GossR.HirboJ.ThompsonS.et al (2014). Origin and differential selection of allelic variation at TAS2R16 associated with salicin bitter taste sensitivity in Africa.Mol. Biol. Evol.31288–302. 10.1093/molbev/mst211

  • CrossRef
  • Google Scholar

• 19

  CantoneE.NegriR.RoscettoE.GrassiaR.CataniaM. R.CapassoP.et al (2018). In vivo biofilm formation, gram-negative infections and TAS2R38 polymorphisms in CRSw NP Patients.Laryngoscope128E339–E345. 10.1002/lary.27175

  • CrossRef
  • Google Scholar

• 20

  CapoteL. A.Mendez PerezR.LymperopoulosA. (2015). GPCR signaling and cardiac function.Eur. J. Pharmacol.763143–148.

  • Google Scholar

• 21

  CappellettiS.PiacentinoD.FineschiV.FratiP.CipolloniL.AromatarioM. (2018). Caffeine-related deaths: manner of deaths and categories at risk.Nutrients10:611. 10.3390/nu10050611

  • CrossRef
  • Google Scholar

• 22

  CareagaG.SalazarD.TellezS.SanchezO.BorrayoG.ArgueroR. (2001). Clinical impact of histidine-ketoglutarate-tryptophan (HTK) cardioplegic solution on the perioperative period in open heart surgery patients.Arch. Med. Res.32296–299. 10.1016/s0188-4409(01)00296-x

  • CrossRef
  • Google Scholar

• 23

  ChandrashekarJ.MuellerK. L.HoonM. A.AdlerE.FengL.GuoW.et al (2000). T2Rs function as bitter taste receptors.Cell100703–711. 10.1016/s0092-8674(00)80706-0

  • CrossRef
  • Google Scholar

• 24

  ChenJ. G.PingN. N.LiangD.LiM. Y.MiY. N.LiS.et al (2017). The expression of bitter taste receptors in mesenteric, cerebral and omental arteries.Life Sci.17016–24. 10.1016/j.lfs.2016.11.010

  • CrossRef
  • Google Scholar

• 25

  ChenH.NweP. K.YangY.RosenC. E.BieleckaA. A.KuchrooM.et al (2019). A forward chemical genetic screen reveals gut microbiota metabolites that modulate host physiology.Cell1771217.e18–1231.e18. 10.1016/j.cell.2019.03.036

  • CrossRef
  • Google Scholar

• 26

  ChewD. S.RezazadehS.MillerR. J. (2017). Recurrent syncope in the emergency department: a lethal cause not for the faint hearted.JAMA Intern. Med.177874–876. 10.1001/jamainternmed.2017.0580

  • CrossRef
  • Google Scholar

• 27

  ChoiJ. H.LeeJ.YangS.KimJ. (2017). Genetic variations in taste perception modify alcohol drinking behavior in Koreans.Appetite113178–186. 10.1016/j.appet.2017.02.022

  • CrossRef
  • Google Scholar

• 28

  ClappT. R.TrubeyK. R.VandenbeuchA.StoneL. M.MargolskeeR. F.ChaudhariN.et al (2008). Tonic activity of Galpha-gustducin regulates taste cell responsivity.FEBS Lett.5823783–3787. 10.1016/j.febslet.2008.10.007

  • CrossRef
  • Google Scholar

• 29

  ClarkA. A.DotsonC. D.ElsonA. E.VoigtA.BoehmU.MeyerhofW.et al (2015). TAS2R bitter taste receptors regulate thyroid function.Faseb J.29164–172. 10.1096/fj.14-262246

  • CrossRef
  • Google Scholar

• 30

  ClarkA. A.LiggettS. B.MungerS. D. (2012). Extraoral bitter taste receptors as mediators of off-target drug effects.FASEB J.264827–4831. 10.1096/fj.12-215087

  • CrossRef
  • Google Scholar

• 31

  CohenL. J.EsterhazyD.KimS.-H.LemetreC.AguilarR. R.GordonE. A.et al (2017). Commensal bacteria make GPCR ligands that mimic human signalling molecules.Nature54948–53. 10.1038/nature25997

  • CrossRef
  • Google Scholar

• 32

  CohenS. P.BuckleyB. K.KosloffM.GarlandA. L.BoschD. E.ChengG.et al (2012). Regulator of G-protein signaling-21 (RGS21) is an inhibitor of bitter gustatory signaling found in lingual and airway epithelia.J. Biol. Chem.28741706–41719. 10.1074/jbc.M112.423806

  • CrossRef
  • Google Scholar

• 33

  ColosimoD. A.KohnJ. A.LuoP. M.PiscottaF. J.HanS. M.PickardA. J.et al (2019). Mapping interactions of microbial metabolites with human g-protein-coupled receptors.Cell Host Microbe26273.e7–282.e7. 10.1016/j.chom.2019.07.002

  • CrossRef
  • Google Scholar

• 34

  DanopoulosE.AngelopoulosB.MoulopoulosS. D.RomanosA. (1954). [Electrocardiographic studies on cardiotoxic effect of quinine in dogs].Z. Kreislaufforsch43856–861.

  • Google Scholar

• 35

  DanzeL. K.LangdorfM. I. (1991). Reversal of orphenadrine-induced ventricular tachycardia with physostigmine.J. Emerg. Med.9453–457. 10.1016/0736-4679(91)90217-4

  • CrossRef
  • Google Scholar

• 36

  DaviesD. G.ParsekM. R.PearsonJ. P.IglewskiB. H.CostertonJ. W.GreenbergE. P. (1998). The involvement of cell-to-cell signals in the development of a bacterial biofilm.Science280295–298. 10.1126/science.280.5361.295

  • CrossRef
  • Google Scholar

• 37

  DemirT.YumrutasO.CengizB.DemiryurekS.UnverdiH.KaplanD. S.et al (2014). Evaluation of TRPM (transient receptor potential melastatin) genes expressions in myocardial ischemia and reperfusion.Mol. Biol. Rep.412845–2849. 10.1007/s11033-014-3139-0

  • CrossRef
  • Google Scholar

• 38

  DesaiM. S.PennyD. J. (2013). Bile acids induce arrhythmias: old metabolite, new tricks.Heart991629–1630. 10.1136/heartjnl-2013-304546

  • CrossRef
  • Google Scholar

• 39

  DeshpandeD. A.WangW. C. H.McilmoyleE. L.RobinettK. S.SchillingerR. M.AnS. S.et al (2010). Bitter taste receptors on airway smooth muscle bronchodilate by a localized calcium flux and reverse obstruction.Nat. Med.161299–1304. 10.1038/nm.2237

  • CrossRef
  • Google Scholar

• 40

  DevillierP.NalineE.Grassin-DelyleS. (2015). The pharmacology of bitter taste receptors and their role in human airways.Pharmacol. Ther.15511–21. 10.1016/j.pharmthera.2015.08.001

  • CrossRef
  • Google Scholar

• 41

  Di PizioA.NivM. Y. (2015). Promiscuity and selectivity of bitter molecules and their receptors.Bioorg. Med. Chem.234082–4091. 10.1016/j.bmc.2015.04.025

  • CrossRef
  • Google Scholar

• 42

  DoddH. J.TatnallF. M.SarkanyI. (1985). Fast atrial fibrillation induced by treatment of psoriasis with azathioprine.Br. Med. J.291:706. 10.1136/bmj.291.6497.706

  • CrossRef
  • Google Scholar

• 43

  DollS.DressenM.GeyerP. E.ItzhakD. N.BraunC.DopplerS. A.et al (2017). Region and cell-type resolved quantitative proteomic map of the human heart.Nat. Commun.8:1469. 10.1038/s41467-017-01747-2

  • CrossRef
  • Google Scholar

• 44

  DotsonC. D.WallaceM. R.BartoshukL. M.LoganH. L. (2012). Variation in the gene TAS2R13 is associated with differences in alcohol consumption in patients with head and neck cancer.Chem. Sen.37737–744. 10.1093/chemse/bjs063

  • CrossRef
  • Google Scholar

• 45

  DotsonC. D. C. D. (2008). Bitter taste receptors influence glucose homeostasis.PloS One3:e3974. 10.1371/journal.pone.0003974

  • CrossRef
  • Google Scholar

• 46

  Dutta BanikD.MartinL. E.FreichelM.TorregrossaA. M.MedlerK. F. (2018). TRPM4 and TRPM5 are both required for normal signaling in taste receptor cells.Proc. Natl. Acad. Sci. U.S.A.115E772–E781. 10.1073/pnas.1718802115

  • CrossRef
  • Google Scholar

• 47

  EdwardsA. C.MeredithT. J.SowtonE. (1978). Complete heart block due to chronic chloroquine toxicity managed with permanent pacemaker.Br. Med. J.11109–1110. 10.1136/bmj.1.6120.1109

  • CrossRef
  • Google Scholar

• 48

  EkoffM.ChoiJ.-H.JamesA.DahlénB.NilssonG.DahlénS.-E. (2014). Bitter taste receptor (TAS2R) agonists inhibit IgE-dependent mast cell activation.J. Allergy Cli. Immunol.134475–478. 10.1016/j.jaci.2014.02.029

  • CrossRef
  • Google Scholar

• 49

  FernandesF. M.SilvaE. P.MartinsR. R.OliveiraA. G. (2018). QTc interval prolongation in critically ill patients: prevalence, risk factors and associated medications.PLoS One13:e0199028. 10.1371/journal.pone.0199028

  • CrossRef
  • Google Scholar

• 50

  FisoneG.BorgkvistA.UsielloA. (2004). Caffeine as a psychomotor stimulant: mechanism of action.Cell Mol. Life Sci.61857–872. 10.1007/s00018-003-3269-3

  • CrossRef
  • Google Scholar

• 51

  FlegelC.ManteniotisS.OstholdS.HattH.GisselmannG. (2013). Expression profile of ectopic olfactory receptors determined by deep sequencing.PloS One8:e55368. 10.1371/journal.pone.0055368

  • CrossRef
  • Google Scholar

• 52

  FosterS. R.BlankK.HoeL. E. S.BehrensM.MeyerhofW.PeartJ. N.et al (2014). Bitter taste receptor agonists elicit G-protein-dependent negative inotropy in the murine heart.Faseb J.284497–4508. 10.1096/fj.14-256305

  • CrossRef
  • Google Scholar

• 53

  FosterS. R.PorrelloE. R.PurdueB.ChanH.-W.VoigtA.FrenzelS.et al (2013). Expression, regulation and putative nutrient-sensing function of taste GPCRs in the heart.PLoS One8:e64579. 10.1371/journal.pone.0064579

  • CrossRef
  • Google Scholar

• 54

  FosterS. R.PorrelloE. R.StefaniM.SmithN. J.MolenaarP.Dos RemediosC. G.et al (2015a). Cardiac gene expression data and in silico analysis provide novel insights into human and mouse taste receptor gene regulation.Naunyn Schmiedeberg’s Arch. Pharmacol.3881009–1027. 10.1007/s00210-015-1118-1

  • CrossRef
  • Google Scholar

• 55

  FosterS. R.RouraE.MolenaarP.ThomasW. G. (2015b). G protein-coupled receptors in cardiac biology: old and new receptors.Biophys. Rev.777–89. 10.1007/s12551-014-0154-2

  • CrossRef
  • Google Scholar

• 56

  FreundJ. R.MansfieldC. J.DoghramjiL. J.AdappaN. D.PalmerJ. N.KennedyD. W.et al (2018). Activation of airway epithelial bitter taste receptors by Pseudomonas aeruginosa quinolones modulates calcium, cyclic-AMP, and nitric oxide signaling.J. Biol. Chem.2939824–9840. 10.1074/jbc.RA117.001005

  • CrossRef
  • Google Scholar

• 57

  GaidaM. M.DapuntU.HanschG. M. (2016a). Sensing developing biofilms: the bitter receptor T2R38 on myeloid cells.Pathog Dis.74:ftw004. 10.1093/femspd/ftw004

  • CrossRef
  • Google Scholar

• 58

  GaidaM. M.MayerC.DapuntU.StegmaierS.SchirmacherP.WabnitzG. H.et al (2016b). Expression of the bitter receptor T2R38 in pancreatic cancer: localization in lipid droplets and activation by a bacteria-derived quorum-sensing molecule.Oncotarget712623–12632. 10.18632/oncotarget.7206

  • CrossRef
  • Google Scholar

• 59

  Garcia-EsparciaP.SchlüterA.CarmonaM.MorenoJ.AnsoleagaB.Torrejón-EscribanoB.et al (2013). Functional genomics reveals dysregulation of cortical olfactory receptors in parkinson disease: novel putative chemoreceptors in the human brain.J. Neuropathol.Exp. Neurol.72524–539. 10.1097/NEN.0b013e318294fd76

  • CrossRef
  • Google Scholar

• 60

  GardinerS. M.ChhabraS. R.HartyC.WilliamsP.PritchardD. I.BycroftB. W.et al (2001). Haemodynamic effects of the bacterial quorum sensing signal molecule, N-(3-oxododecanoyl)-L-homoserine lactone, in conscious, normal and endotoxaemic rats.Br. J. Pharmacol.1331047–1054. 10.1038/sj.bjp.0704174

  • CrossRef
  • Google Scholar

• 61

  GentiluomoM.CrifasiL.LuddiA.LocciD.BaraleR.PiomboniP.et al (2017). Taste receptor polymorphisms and male infertility.Hum. Reprod.322324–2331. 10.1093/humrep/dex305

  • CrossRef
  • Google Scholar

• 62

  GilS.ColdwellS.DruryJ. L.ArroyoF.PhiT.SaadatS.et al (2015). Genotype-Specific Regulation of Oral Innate Immunity by T2R38 Taste Receptor.Mol. Immunol.68663–670. 10.1016/j.molimm.2015.10.012

  • CrossRef
  • Google Scholar

• 63

  GiudicessiJ. R.AckermanM. J.CamilleriM. (2018). Cardiovascular safety of prokinetic agents: a focus on drug-induced arrhythmias.Neurogastroenterol. Motil.30:e13302. 10.1111/nmo.13302

  • CrossRef
  • Google Scholar

• 64

  Grassin DelyleS.AbrialC.BrolloM.Fayad-KobeissiS.NalineE.DevillierP. (2014). “Characterization of the expression and the role of bitter taste receptors in human lung parenchyma and macrophages,” in D36. Sepsis, Acute Respiratory Distress Syndrome, and Acute Lung Injury, (New York, NY: American Thoracic Society), A5749–A5749.

  • Google Scholar

• 65

  Grassin-DelyleS.AbrialC.Fayad-KobeissiS.BrolloM.FaisyC.AlvarezJ.-C.et al (2013). The expression and relaxant effect of bitter taste receptors in human bronchi.Respir. Res.14134–134. 10.1186/1465-9921-14-134

  • CrossRef
  • Google Scholar

• 66

  GuinamardR.ChatelierA.DemionM.PotreauD.PatriS.RahmatiM.et al (2004). Functional characterization of a Ca(2+)-activated non-selective cation channel in human atrial cardiomyocytes.J. Physiol.55875–83. 10.1113/jphysiol.2004.063974

  • CrossRef
  • Google Scholar

• 67

  GuleriA.KumarA.MorganR. J.HartleyM.RobertsD. H. (2012). Anaphylaxis to chlorhexidine-coated central venous catheters: a case series and review of the literature.Surg. Infect.13171–174. 10.1089/sur.2011.011

  • CrossRef
  • Google Scholar

• 68

  HagueC.UbertiM. A.ChenZ.BushC. F.JonesS. V.ResslerK. J.et al (2004). Olfactory receptor surface expression is driven by association with the β&ltsub&gt2&lt/sub&gt-adrenergic receptor.Proc. Natl.Acad. Sci. U.S.A.101:13672. 10.1073/pnas.0403854101

  • CrossRef
  • Google Scholar

• 69

  HayesJ. E.WallaceM. R.KnopikV. S.HerbstmanD. M.BartoshukL. M.DuffyV. B. (2011). Allelic variation in TAS2R bitter receptor genes associates with variation in sensations from and ingestive behaviors toward common bitter beverages in adults.Chem. Sens.36311–319. 10.1093/chemse/bjq132

  • CrossRef
  • Google Scholar

• 70

  HeiserJ. M.DayaM. R.MagnussenA. R.NortonR. L.SpykerD. A.AllenD. W.et al (1992). Massive strychnine intoxication: serial blood levels in a fatal case.J. Toxicol. Clin. Toxicol.30269–283. 10.3109/15563659209038638

  • CrossRef
  • Google Scholar

• 71

  HinrichsA. L.WangJ. C.BufeB.KwonJ. M.BuddeJ.AllenR.et al (2006). Functional variant in a bitter-taste receptor (hTAS2R16) influences risk of alcohol dependence.Am. J. Hum. Genet.78103–111. 10.1086/499253

  • CrossRef
  • Google Scholar

• 72

  HuangL.ShankerY. G.DubauskaiteJ.ZhengJ. Z.YanW.RosenzweigS.et al (1999). Ggamma13 colocalizes with gustducin in taste receptor cells and mediates IP3 responses to bitter denatonium.Nat. Neurosci.21055–1062. 10.1038/15981

  • CrossRef
  • Google Scholar

• 73

  HudsonJ.TitmarshD.HidalgoA.WolvetangE.Cooper-WhiteJ. (2012). Primitive cardiac cells from human embryonic stem cells.Stem Cells Dev.211513–1523. 10.1089/scd.2011.0254

  • CrossRef
  • Google Scholar

• 74

  IhamaY.AgedaS.FukeC.MiyazakiT. (2007). Autopsy case of aspirin intoxication: distribution of salicylic acid and salicyluric acid in body fluid and organs.Chudoku Kenkyu20375–380.

  • Google Scholar

• 75

  IsbergV.MordalskiS.MunkC.RatajK.HarpsoeK.HauserA. S.et al (2016). GPCRdb: an information system for G protein-coupled receptors.Nucleic Acids Res.44D356–D364. 10.1093/nar/gkw1218

  • CrossRef
  • Google Scholar

• 76

  IvanovaA. A.MaksimovV. N.OrlovP. S.IvanoshchukD. E.SavchenkoS. V.VoevodaM. I. (2017). Association of the genetic markers for myocardial infarction with sudden cardiac death.Indian Heart J.69(Suppl. 1), S8–S11. 10.1016/j.ihj.2016.07.016

  • CrossRef
  • Google Scholar

• 77

  JaggupilliA.HowardR.UpadhyayaJ. D.BhullarR. P.ChelikaniP. (2016). Bitter taste receptors: novel insights into the biochemistry and pharmacology.Int. J. Biochem. Cell Biol.77184–196. 10.1016/j.biocel.2016.03.005

  • CrossRef
  • Google Scholar

• 78

  JaggupilliA.SinghN.UpadhyayaJ.SikarwarA. S.ArakawaM.DakshinamurtiS.et al (2017). Analysis of the expression of human bitter taste receptors in extraoral tissues.Mol. Cell Biochem.426137–147. 10.1007/s11010-016-2902-z

  • CrossRef
  • Google Scholar

• 79

  JeonT.-I.SeoY.-K.OsborneT. F. (2011). Gut bitter taste receptor signalling induces ABCB1 through a mechanism involving CCK.Biochem. J.43833–37. 10.1042/BJ20110009

  • CrossRef
  • Google Scholar

• 80

  JiM.SuX.SuX.ChenY.HuangW.ZhangJ.et al (2014). Identification of novel compounds for human bitter taste receptors.Chem. Biol. Drug Des.8463–74. 10.1111/cbdd.12293

  • CrossRef
  • Google Scholar

• 81

  KajiI.KarakiS.FukamiY.TerasakiM.KuwaharaA. (2009). Secretory effects of a luminal bitter tastant and expressions of bitter taste receptors, T2Rs, in the human and rat large intestine.Am. J. Physiol. Gastrointest. Liver Physiol.296G971–G981. 10.1152/ajpgi.90514.2008

  • CrossRef
  • Google Scholar

• 82

  KangK. S.KimH. I.KimO. H.ChaK. C.KimH.LeeK. H.et al (2016). Clinical outcomes of adverse cardiovascular events in patients with acute dapsone poisoning.Clin. Exp. Emerg. Med.341–45. 10.15441/ceem.15.088

  • CrossRef
  • Google Scholar

• 83

  KaplanB.BuchananJ.KrantzM. J. (2011). QTc prolongation due to dextromethorphan.Int. J. Cardiol.148363–364.

  • Google Scholar

• 84

  KimD.PauerS. H.YongH. M.AnS. S.LiggettS. B. (2016). beta2-adrenergic receptors chaperone trapped bitter taste receptor 14 to the cell surface as a heterodimer and exert unidirectional desensitization of taste receptor function.J. Biol. Chem.29117616–17628. 10.1074/jbc.M116.722736

  • CrossRef
  • Google Scholar

• 85

  KimD.WooJ. A.GeffkenE.AnS. S.LiggettS. B. (2017). Coupling of airway smooth muscle bitter taste receptors to intracellular signaling and relaxation is via galphai1,2,3.Am. J. Respir. Cell Mol. Biol.56762–771. 10.1165/rcmb.2016-0373OC

  • CrossRef
  • Google Scholar

• 86

  KimU.WoodingS.RicciD.JordeL. B.DraynaD. (2005). Worldwide haplotype diversity and coding sequence variation at human bitter taste receptor loci.Hum. Mutat26199–204. 10.1002/humu.20203

  • CrossRef
  • Google Scholar

• 87

  KirchW.HalabiA.LindeM.SantosS. R.OhnhausE. E. (1989). Negative effects of famotidine on cardiac performance assessed by noninvasive hemodynamic measurements.Gastroenterology961388–1392. 10.1016/0016-5085(89)90503-9

  • CrossRef
  • Google Scholar

• 88

  KochW.HoppmannP.SchomigA.KastratiA. (2011). Variations of specific non-candidate genes and risk of myocardial infarction: a replication study.Int. J. Cardiol.14738–41. 10.1016/j.ijcard.2009.07.028

  • CrossRef
  • Google Scholar

• 89

  KongH.JonesP. P.KoopA.ZhangL.DuffH. J.ChenS. R. (2008). Caffeine induces Ca2+ release by reducing the threshold for luminal Ca2+ activation of the ryanodine receptor.Biochem. J.414441–452. 10.1042/BJ20080489

  • CrossRef
  • Google Scholar

• 90

  KuhnC.BufeB.BatramC.MeyerhofW. (2010). Oligomerization of TAS2R bitter taste receptors.Chem. Senses35395–406. 10.1093/chemse/bjq027

  • CrossRef
  • Google Scholar

• 91

  LabarinasS.MeulmesterK.GreeneS.ThomasJ.VirkM.ErkonenG. (2018). Extracorporeal cardiopulmonary resuscitation after diphenhydramine ingestion.J. Med. Toxicol.14253–256. 10.1007/s13181-018-0672-6

  • CrossRef
  • Google Scholar

• 92

  LagerstromM. C.SchiothH. B. (2008). Structural diversity of G protein-coupled receptors and significance for drug discovery.Nat. Rev. Drug Discov.7339–357. 10.1038/nrd2518

  • CrossRef
  • Google Scholar

• 93

  LauG. (1995). A fatal case of drug-induced multi-organ damage in a patient with Hansen’s disease: dapsone syndrome or rifampicin toxicity?Forensic. Sci. Int.73109–115. 10.1016/0379-0738(95)01719-y

  • CrossRef
  • Google Scholar

• 94

  LeeK. W.KayserS. R.HongoR. H.TsengZ. H.ScheinmanM. M. (2004). Famotidine and long QT syndrome.Am. J. Cardiol.931325–1327. 10.1016/j.amjcard.2004.02.025

  • CrossRef
  • Google Scholar

• 95

  LeeR. J.ChenB.ReddingK. M.MargolskeeR. F.CohenN. A. (2014). Mouse nasal epithelial innate immune responses to Pseudomonas aeruginosa quorum-sensing molecules require taste signaling components.Innate Immun.20606–617. 10.1177/1753425913503386

  • CrossRef
  • Google Scholar

• 96

  LeeR. J.XiongG.KofonowJ. M.ChenB.LysenkoA.JiangP.et al (2012). T2R38 taste receptor polymorphisms underlie susceptibility to upper respiratory infection.J. Clin. Invest.1224145–4159. 10.1172/JCI64240

  • CrossRef
  • Google Scholar

• 97

  LeeT. M.LiR. C.ChaiC. Y. (1974). Effects of diphenylhydantoin on cardiac arrhythmias induced by picrotoxin. Chin. J. Physiol.21, 219–229.

  • Google Scholar

• 98

  LeeT. M.YangK. L.KuoJ. S.ChaiC. Y. (1972). Importance of sympathetic mechanism on cardiac arrhythmias induced by picrotoxin. Exp. Neurol.36, 389–398.

  • Google Scholar

• 99

  LeiY.ZhengM. H.HuangW.ZhangJ.LuY. (2018). Wet beriberi with multiple organ failure remarkably reversed by thiamine administration: a case report and literature review.Medicine97:e0010. 10.1097/MD.0000000000010010

  • CrossRef
  • Google Scholar

• 100

  LinC. J.ChenY. T.KuoJ. S.LeeA. Y. (1992). Antiarrhythmic action of naloxone. Suppression of picrotoxin-induced cardiac arrhythmias in the rat.Jpn. Heart. J.33365–372. 10.1536/ihj.33.365

  • CrossRef
  • Google Scholar

• 101

  LisztK. I.LeyJ. P.LiederB.BehrensM.StögerV.ReinerA.et al (2017). Caffeine induces gastric acid secretion via bitter taste signaling in gastric parietal cells.Proc. Natl. Acad. Sci. U.S.A.114:E6260. 10.1073/pnas.1703728114

  • CrossRef
  • Google Scholar

• 102

  LiuA. M.HoM. K.WongC. S.ChanJ. H.PauA. H.WongY. H. (2003). Galpha(16/z) chimeras efficiently link a wide range of G protein-coupled receptors to calcium mobilization.J. Biomol. Screen839–49. 10.1177/1087057102239665

  • CrossRef
  • Google Scholar

• 103

  LiuM.QianW.SubramaniyamS.LiuS.XinW. (2020). Denatonium enhanced the tone of denuded rat aorta via bitter taste receptor and phosphodiesterase activation.Eur. J. Pharmacol.872:172951. 10.1016/j.ejphar.2020.172951

  • CrossRef
  • Google Scholar

• 104

  LocontoJ.PapesF.ChangE.StowersL.JonesE. P.TakadaT.et al (2003). Functional expression of murine V2R pheromone receptors involves selective association with the M10 and M1 families of MHC Class Ib Molecules.Cell112607–618. 10.1016/s0092-8674(03)00153-3

  • CrossRef
  • Google Scholar

• 105

  LokeW. M.HodgsonJ. M.ProudfootJ. M.MckinleyA. J.PuddeyI. B.CroftK. D. (2008). Pure dietary flavonoids quercetin and (-)-epicatechin augment nitric oxide products and reduce endothelin-1 acutely in healthy men.Am. J. Clin. Nutr.881018–1025. 10.1093/ajcn/88.4.1018

  • CrossRef
  • Google Scholar

• 106

  LossowK.HubnerS.RoudnitzkyN.SlackJ. P.PollastroF.BehrensM.et al (2016). Comprehensive analysis of mouse bitter taste receptors reveals different molecular receptive ranges for orthologous receptors in mice and humans.J. Biol. Chem.29115358–15377. 10.1074/jbc.M116.718544

  • CrossRef
  • Google Scholar

• 107

  LuP.ZhangC.-H.LifshitzL. M.ZhugeR. (2017). Extraoral bitter taste receptors in health and disease.149181–119. 10.1085/jgp.201611637

  • CrossRef
  • Google Scholar

• 108

  LuZ. K.YuanJ.LiM.SuttonS. S.RaoG. A.JacobS.et al (2015). Cardiac risks associated with antibiotics: azithromycin and levofloxacin.Expert. Opin. Drug. Saf.14295–303. 10.1517/14740338.2015.989210

  • CrossRef
  • Google Scholar

• 109

  LundT. C.KobsA. J.KramerA.NyquistM.KurokiM. T.OsbornJ.et al (2013). Bone marrow stromal and vascular smooth muscle cells have chemosensory capacity via bitter taste receptor expression.PLoS One8:e58945. 10.1371/journal.pone.0058945

  • CrossRef
  • Google Scholar

• 110

  LuzzaF.RaffaS.SaporitoF.OretoG. (2006). Torsades de pointes in congenital long QT syndrome following low-dose orphenadrine.Int. J. Clin. Pract.60606–608. 10.1111/j.1368-5031.2006.00764.x

  • CrossRef
  • Google Scholar

• 111

  MacleodJ. G.PhillipsL. (1947). Hypersensitivity to colchicine.Ann. Rheum. Dis.6224–229.

  • Google Scholar

• 112

  MaliziaE.SarcinelliL.PascarellaM.AmbrosiniM.SmeriglioM.RussoA. (1980). Cardiotoxicity from orphenadrine intoxication in humans.Arch. Toxicol. Suppl.4425–427. 10.1007/978-3-642-67729-8_98

  • CrossRef
  • Google Scholar

• 113

  MannaertsD.FaesE.GoovaertsI.StoopT.CornetteJ.GyselaersW.et al (2017). Flow-mediated dilation and peripheral arterial tonometry are disturbed in preeclampsia and reflect different aspects of endothelial function.Am. J. Physiol. Regul. Integr. Comp. Physiol.313R518–R525. 10.1152/ajpregu.00514.2016

  • CrossRef
  • Google Scholar

• 114

  MansonM. L.SäfholmJ.Al-AmeriM.BergmanP.OrreA.-C.SwärdK.et al (2014). Bitter taste receptor agonists mediate relaxation of human and rodent vascular smooth muscle.Eur. J. Pharmacol.740302–311. 10.1016/j.ejphar.2014.07.005

  • CrossRef
  • Google Scholar

• 115

  MartinL. T. P.NachtigalM. W.SelmanT.NguyenE.SalsmanJ.DellaireG.et al (2018). Bitter taste receptors are expressed in human epithelial ovarian and prostate cancers cells and noscapine stimulation impacts cell survival.Mol. Cell. Biochem.454203–214. 10.1007/s11010-018-3464-z

  • CrossRef
  • Google Scholar

• 116

  Martin-FernandezB.De Las HerasN.Valero-MunozM.BallesterosS.YaoY. Z.StantonP. G.et al (2014). Beneficial effects of proanthocyanidins in the cardiac alterations induced by aldosterone in rat heart through mineralocorticoid receptor blockade.PLoS One9:e111104. 10.1371/journal.pone.0111104

  • CrossRef
  • Google Scholar

• 117

  McClintockT. S.LandersT. M.GimelbrantA. A.FullerL. Z.JacksonB. A.JayawickremeC. K.et al (1997). Functional expression of olfactory-adrenergic receptor chimeras and intracellular retention of heterologously expressed olfactory receptors.Brain Res. Mol. Brain Res.48270–278. 10.1016/s0169-328x(97)00099-5

  • CrossRef
  • Google Scholar

• 118

  MeyerhofW. (2005). Elucidation of mammalian bitter taste.Rev. Physiol. Biochem. Pharmacol.15437–72.

  • Google Scholar

• 119

  MeyerhofW.BatramC.KuhnC.BrockhoffA.ChudobaE.BufeB.et al (2010). The molecular receptive ranges of human TAS2R bitter taste receptors.Chem. Sen.35157–170.

  • Google Scholar

• 120

  Meyer-MassettiC.ChengC. M.SharpeB. A.MeierC. R.GuglielmoB. J. (2010). The FDA extended warning for intravenous haloperidol and torsades de pointes: how should institutions respond?J. Hosp. Med,.5E8–E16.

  • Google Scholar

• 121

  Mfuna EndamL.Filali-MouhimA.BoisvertP.BouletL.-P.BosséY.DesrosiersM. (2014). Genetic variations in taste receptors are associated with chronic rhinosinusitis: a replication study.Int. Forum Allergy Rhinol.4200–206.

  • Google Scholar

• 122

  MikolajczykT. P.NosalskiR.SkibaD. S.KoziolJ.MazurM.Justo-JuniorA. S.et al (2019). 1,2,3,4,6-Penta-O-galloyl-beta-d-glucose modulates perivascular inflammation and prevents vascular dysfunction in angiotensin II-induced hypertension.Br. J. Pharmacol.1761951–1965.

  • Google Scholar

• 123

  MinaY.Rinkevich-ShopS.KonenE.GoiteinO.KushnirT.EpsteinF. H.et al (2013). Mast cell inhibition attenuates myocardial damage, adverse remodeling, and dysfunction during fulminant myocarditis in the rat.J. Cardiovasc. Pharmacol. Ther.18152–161.

  • Google Scholar

• 124

  MiyamoriI.SakaiT.ItoT.SugiharaN.IkedaM.TakedaY.et al (1985). Reversible hyperkalemia induced by flufenamic acid in asymptomatic hyporeninemic patient.Jpn. J. Med.24269–272.

  • Google Scholar

• 125

  MoralesM. A.SilvaA.BritoG.BustamanteS.PonceH.PaeileC. (1995). Vasorelaxant effect of the analgesic clonixin on rat aorta.Gen. Pharmacol.26425–430.

  • Google Scholar

• 126

  Morales-SotoN.DunhamS. J. B.BaigN. F.EllisJ. F.MadukomaC. S.BohnP. W.et al (2018). Spatially dependent alkyl quinolone signaling responses to antibiotics in Pseudomonas aeruginosa swarms. J. Biol. Chem.293, 9544—9552. 10.1074/jbc.RA118.002605

  • CrossRef
  • Google Scholar

• 127

  MoreiraI. S. (2014). Structural features of the G-protein/GPCR interactions.Biochim. Biophys. Acta Gen. Subj.184016–33.

  • Google Scholar

• 128

  MuellerK. L.HoonM. A.ErlenbachI.ChandrashekarJ.ZukerC. S.RybaN. J. (2005). The receptors and coding logic for bitter taste.Nature434225–229.

  • Google Scholar

• 129

  MukerjiV.AlpertM. A.FlakerG. C.BeachC. L.WeberR. D. (1986). Cardiac conduction abnormalities and atrial arrhythmias associated with salicylate toxicity.Pharmacotherapy641–43.

  • Google Scholar

• 130

  NakanishiM.AndoH.WatanabeN.KitamuraK.ItoK.OkayamaH.et al (2000). Identification and characterization of human Wee1B, a new member of the Wee1 family of Cdk-inhibitory kinases.Genes Cells5839–847.

  • Google Scholar

• 131

  NiaA. M.FuhrU.GassanovN.ErdmannE.ErF. (2010). Torsades de pointes tachycardia induced by common cold compound medication containing chlorpheniramine.Eur. J. Clin. Pharmacol.661173–1175.

  • Google Scholar

• 132

  NishinoT.WakaiS.AokiH.InokuchiS. (2018). Cardiac arrest caused by diphenhydramine overdose.Acute Med. Surg.5380–383.

  • Google Scholar

• 133

  NowakS.Di PizioA.LevitA.NivM. Y.MeyerhofW.BehrensM. (2018). Reengineering the ligand sensitivity of the broadly tuned human bitter taste receptor TAS2R14.Biochim. Biophys. Acta Gen. Subj.18622162–2173.

  • Google Scholar

• 134

  NugrahaB.BuonoM. F.Von BoehmerL.HoerstrupS. P.EmmertM. Y. (2019). Human cardiac organoids for disease modeling.Clin. Pharmacol. Ther.10579–85.

  • Google Scholar

• 135

  OkeahialamB. N. (2015). Cardiac dysrhythmia resulting from antibiotic abuse.Niger. Med. J.56429–432.

  • Google Scholar

• 136

  Orsmark-PietrasC.JamesA.KonradsenJ. R.NordlundB.SoderhallC.PulkkinenV.et al (2013). Transcriptome analysis reveals upregulation of bitter taste receptors in severe asthmatics.Eur. Respir. J.4265–78.

  • Google Scholar

• 137

  OrtizM.MartinA.ArribasF.Coll-VinentB.Del ArcoC.PeinadoR.et al (2017). Randomized comparison of intravenous procainamide vs. intravenous amiodarone for the acute treatment of tolerated wide QRS tachycardia: the PROCAMIO study.Eur. Heart J.381329–1335.

  • Google Scholar

• 138

  OsadchiiO. E. (2018). Effects of antiarrhythmics and hypokalemia on the rate adaptation of cardiac repolarization.Scand. Cardiovasc. J.52218–226.

  • Google Scholar

• 139

  OzeckM.BrustP.XuH.ServantG. (2004). Receptors for bitter, sweet and umami taste couple to inhibitory G protein signaling pathways.Eur. J. Pharmacol.489139–149.

  • Google Scholar

• 140

  PapageorgiouN.BriasoulisA.LazarosG.ImazioM.TousoulisD. (2017). Colchicine for prevention and treatment of cardiac diseases: a meta-analysis.Cardiovasc. Ther.3510–18.

  • Google Scholar

• 141

  PedrettiR. F.ColomboE.Sarzi BragaS.BallardiniL.CaruB. (1995). Effects of oral pirenzepine on heart rate variability and baroreceptor reflex sensitivity after acute myocardial infarction.J. Am. Coll Cardiol.25915–921.

  • Google Scholar

• 142

  PereraR. K.FischerT. H.WagnerM.DewenterM.VettelC.BorkN. I.et al (2017). Atropine augments cardiac contractility by inhibiting cAMP-specific phosphodiesterase type 4.Sci. Rep.7:15222.

  • Google Scholar

• 143

  PerkinsA.MarillK. (2012). Accelerated AV nodal conduction with use of procainamide in atrial fibrillation.J. Emerg. Med.42e47–e50.

  • Google Scholar

• 144

  Pinto-ScognamiglioW. (1968). Effects of thujone on spontaneous activity and on conditioned behavior of rats.Boll. Chim. Farm.107780–791.

  • Google Scholar

• 145

  PluznickJ. L.ProtzkoR. J.GevorgyanH.PeterlinZ.SiposA.HanJ.et al (2013). Olfactory receptor responding to gut microbiota-derived signals plays a role in renin secretion and blood pressure regulation.Proc. Natl.Acad. Sci.110:4410.

  • Google Scholar

• 146

  PonrajL.MishraA. K.KoshyM.CareyR. A. B. (2017). A rare case report of Strychnos nux-vomica poisoning with bradycardia.J. Fam. Med. Prim. Care6663–665.

  • Google Scholar

• 147

  PostmaD. F.SpitoniC.Van WerkhovenC. H.Van EldenL. J. R.OosterheertJ. J.BontenM. J. M. (2019). Cardiac events after macrolides or fluoroquinolones in patients hospitalized for community-acquired pneumonia: post-hoc analysis of a cluster-randomized trial.BMC Infect. Dis.19:17.

  • Google Scholar

• 148

  RainerP. P.PrimessnigU.HarenkampS.DoleschalB.WallnerM.FaulerG.et al (2013). Bile acids induce arrhythmias in human atrial myocardium–implications for altered serum bile acid composition in patients with atrial fibrillation.Heart991685–1692.

  • Google Scholar

• 149

  ReedD. R.ZhuG.BreslinP. A. S.DukeF. F.HendersA. K.CampbellM. J.et al (2010). The perception of quinine taste intensity is associated with common genetic variants in a bitter receptor cluster on chromosome 12.Hum. Mol. Genet.194278–4285.

  • Google Scholar

• 150

  ReichlingC.MeyerhofW.BehrensM. (2008). Functions of human bitter taste receptors depend on N-glycosylation.J. Neurochem.1061138–1148.

  • Google Scholar

• 151

  RissoD.MoriniG.PaganiL.QuagliarielloA.GiulianiC.De FantiS.et al (2014). Genetic signature of differential sensitivity to stevioside in the Italian population.Genes Nutr.9:401.

  • Google Scholar

• 152

  RissoD. S.GiulianiC.AntinucciM.MoriniG.GaragnaniP.TofanelliS.et al (2017). A bio-cultural approach to the study of food choice: the contribution of taste genetics, population and culture.Appetite114240–247.

  • Google Scholar

• 153

  RohatgiG.RissmillerD. J.GormanJ. M. (2005). Treatment of carisoprodol dependence: a case report.J. Psychiatr. Pract.11347–352.

  • Google Scholar

• 154

  RoudnitzkyN.RissoD.DraynaD.BehrensM.MeyerhofW.WoodingS. P. (2016). Copy number variation in TAS2R bitter taste receptor genes: structure. origin, and population genetics.Chem. Sen.41649–659.

  • Google Scholar

• 155

  RozengurtN.WuS. V.ChenM. C.HuangC.SterniniC.RozengurtE. (2006). Colocalization of the alpha-subunit of gustducin with PYY and GLP-1 in L cells of human colon.Am. J. Physiol. Gastrointest Liver Physiol.291G792–G802.

  • Google Scholar

• 156

  Ruiz-AvilaL.WongG. T.DamakS.MargolskeeR. F. (2001). Dominant loss of responsiveness to sweet and bitter compounds caused by a single mutation in α-gustducin.Proc. Natl. Acad. Sci. U.S.A.98:8868.

  • Google Scholar

• 157

  RussoV.PuzioG.SiniscalchiN. (2006). Azithromycin-induced QT prolongation in elderly patient.Acta Biomed.7730–32.

  • Google Scholar

• 158

  SalemJ. E.AlexandreJ.BachelotA.Funck-BrentanoC. (2016). Influence of steroid hormones on ventricular repolarization.Pharmacol. Ther.16738–47.

  • Google Scholar

• 159

  SantoneD. J.ShahaniR.RubinB. B.RomaschinA. D.LindsayT. F. (2008). Mast cell stabilization improves cardiac contractile function following hemorrhagic shock and resuscitation.Am. J. Physiol. Heart Circ. Physiol.294H2456–H2464.

  • Google Scholar

• 160

  SchoenwaldP. K.SprungJ.AbdelmalakB.MraovicB.TetzlaffJ. E.GurmH. S. (1999). Complete atrioventricular block and cardiac arrest following intravenous famotidine administration.Anesthesiology90623–626.

  • Google Scholar

• 161

  SchroeterH.HeissC.BalzerJ.KleinbongardP.KeenC. L.HollenbergN. K.et al (2006). (-)-Epicatechin mediates beneficial effects of flavanol-rich cocoa on vascular function in humans.Proc. Natl. Acad. Sci. US.A.1031024–1029.

  • Google Scholar

• 162

  SerbanM. C.SahebkarA.ZanchettiA.MikhailidisD. P.HowardG.AntalD.et al (2016). Effects of quercetin on blood pressure: a systematic review and meta-analysis of randomized controlled trials.J. Am. Heart Assoc.5:e002713.

  • Google Scholar

• 163

  ShahA. S.Ben-ShaharY.MoningerT. O.KlineJ. N.WelshM. J. (2009). Motile cilia of human airway epithelia are chemosensory.Science3251131–1134.

  • Google Scholar

• 164

  ShawL.MansfieldC.ColquittL.LinC.FerreiraJ.EmmetsbergerJ.et al (2018). Personalized expression of bitter ‘taste’ receptors in human skin.PLoS One13:e0205322. 10.1371/journal.pone.0205322

  • CrossRef
  • Google Scholar

• 165

  ShiffmanD.EllisS. G.RowlandC. M.MalloyM. J.LukeM. M.IakoubovaO. A.et al (2005). Identification of four gene variants associated with myocardial infarction.Am. J. Hum. Genet.77596–605.

  • Google Scholar

• 166

  ShiffmanD.O’mearaE. S.BareL. A.RowlandC. M.LouieJ. Z.ArellanoA. R.et al (2008). Association of gene variants with incident myocardial infarction in the Cardiovascular Health Study.Arterioscler. Thromb. Vasc. Biol.28173–179.

  • Google Scholar

• 167

  ShimamuraM.HazatoT.AshinoH.YamamotoY.IwasakiE.TobeH.et al (2001). Inhibition of angiogenesis by humulone, a bitter acid from beer hop.Biochem. Biophys. Res. Commun.289220–224.

  • Google Scholar

• 168

  SingerM.DeutschmanC. S.SeymourC. W.Shankar-HariM.AnnaneD.BauerM.et al (2016). The third international consensus definitions for sepsis and septic shock (Sepsis-3).Jama315801–810.

  • Google Scholar

• 169

  SinghN.ChakrabortyR.BhullarR. P.ChelikaniP. (2014). Differential expression of bitter taste receptors in non-cancerous breast epithelial and breast cancer cells.Biochem. Biophys. Res. Commun.446499–503.

  • Google Scholar

• 170

  SoongP. L.TiburcyM.ZimmermannW. H. (2012). Cardiac differentiation of human embryonic stem cells and their assembly into engineered heart muscle.Curr. Protoc. Cell Biol. Chapter23:Unit23.28.

  • Google Scholar

• 171

  SoranzoN.BufeB.SabetiP. C.WilsonJ. F.WealeM. E.MarguerieR.et al (2005). Positive selection on a high-sensitivity allele of the human bitter-taste receptor TAS2R16.Curr. Biol.151257–1265.

  • Google Scholar

• 172

  StasP.FaesD.NoyensP. (2008). Conduction disorder and QT prolongation secondary to long-term treatment with chloroquine.Int. J. Cardiol.127e80–e82.

  • Google Scholar

• 173

  SternL.GieseN.HackertT.StrobelO.SchirmacherP.FelixK.et al (2018). Overcoming chemoresistance in pancreatic cancer cells: role of the bitter taste receptor T2R10.J. Cancer9711–725.

  • Google Scholar

• 174

  SuarezC. R.OwE. P. (1992). Chloramphenicol toxicity associated with severe cardiac dysfunction.Pediatr. Cardiol.1348–51.

  • Google Scholar

• 175

  SutherlandJ. M. (1959). Fatal cardiovascular collapse of infants receiving large amounts of chloramphenicol.JAMA Pediatr.97761–767.

  • Google Scholar

• 176

  TelohJ. K.DohleD. S.PetersenM.VerhaeghR.WaackI. N.RoehrbornF.et al (2016). Histidine and other amino acids in blood and urine after administration of Bretschneider solution (HTK) for cardioplegic arrest in patients: effects on N-metabolism.Amino Acids481423–1432.

  • Google Scholar

• 177

  TepperB. J.KoellikerY.ZhaoL.UllrichN. V.LanzaraC.D’adamoP.et al (2008). Variation in the bitter-taste receptor gene TAS2R38, and adiposity in a genetically isolated population in Southern Italy.Obesity162289–2295.

  • Google Scholar

• 178

  ThompsonP. L. (2019). Colchicine in cardiovascular disease: repurposing an ancient gout drug.Clin. Ther.418–10.

  • Google Scholar

• 179

  TirziuD.GiordanoF. J.SimonsM. (2010). Cell communications in the heart.Circulation122928–937.

  • Google Scholar

• 180

  TonnesmannE.KandolfR.LewalterT. (2013). Chloroquine cardiomyopathy - a review of the literature.Immunopharmacol. Immunotoxicol.35434–442.

  • Google Scholar

• 181

  TranH. T. T.HerzC.RufP.StetterR.LamyE. (2018). Human t2r38 bitter taste receptor expression in resting and activated lymphocytes.Front. Immunol.9:2949. 10.3389/fimmu.2018.02949

  • CrossRef
  • Google Scholar

• 182

  TrifiroG.De RidderM.SultanaJ.OteriA.RijnbeekP.PecchioliS.et al (2017). Use of azithromycin and risk of ventricular arrhythmia.Cmaj189E560–E568.

  • Google Scholar

• 183

  TsygankovaV. O.LozhkinaG. N.KhasanovaH. M.KuimovD. A.RaginoI. Y.MaksimovN. V.et al (2017). Multifactorial prognostication of remote outcomes in patients with Non-ST Elevation acute coronary syndrome.Kardiologiia5728–33.

  • Google Scholar

• 184

  UedaT.UgawaS.YamamuraH.ImaizumiY.ShimadaS. (2003). Functional interaction between T2R taste receptors and G-protein alpha subunits expressed in taste receptor cells.J. Neurosci.237376–7380.

  • Google Scholar

• 185

  UhlenM.FagerbergL.HallstromB. M.LindskogC.OksvoldP.MardinogluA.et al (2015). Proteomics. Tissue-based map of the human proteome.Science347:1260419.

  • Google Scholar

• 186

  UpadhyayaJ.SinghN.BhullarR. P.ChelikaniP. (2015). The structure–function role of C-terminus in human bitter taste receptor T2R4 signaling.Biochim. Biophys. Acta Biomembr.18481502–1508.

  • Google Scholar

• 187

  UpadhyayaJ. D.SinghN.SikarwarA. S.ChakrabortyR.PydiS. P.BhullarR. P.et al (2014). Dextromethorphan mediated bitter taste receptor activation in the pulmonary circuit causes vasoconstriction.PLoS One9:e110373. 10.1371/journal.pone.0110373

  • CrossRef
  • Google Scholar

• 188

  VanherweghemJ. L. (1997). Association of valvular heart disease with Chinese-herb nephropathy.Lancet350:1858.

  • Google Scholar

• 189

  VerbeurgtC.VeithenA.CarlotS.TarabichiM.DumontJ. E.HassidS.et al (2017). The human bitter taste receptor T2R38 is broadly tuned for bacterial compounds.PLoS One12:e0181302. 10.1371/journal.pone.0181302

  • CrossRef
  • Google Scholar

• 190

  VeselyP.StracinaT.HlavacovaM.HalamekJ.KolarovaJ.OlejnickovaV.et al (2019). Haloperidol affects coupling between QT and RR intervals in guinea pig isolated heart.J. Pharmacol. Sci.13923–28.

  • Google Scholar

• 191

  VoK. T.HorngH.SmollinC. G.BenowitzN. L. (2017). Severe carisoprodol withdrawal After a 14-year addiction and acute overdose.J. Emerg. Med.52680–683.

  • Google Scholar

• 192

  VukajlovicD. D.GuettlerN.MiricM.PitschnerH. F. (2006). Effects of atropine and pirenzepine on heart rate turbulence.Ann. Noninvasive Electrocardiol.1134–37.

  • Google Scholar

• 193

  WangJ.GareriC.Rockman HowardA. (2018). G-protein–coupled receptors in heart disease.Circ. Res.123716–735.

  • Google Scholar

• 194

  WangY.YuX.WangF.WangY.WangY.LiH.et al (2013). Yohimbine promotes cardiac NE release and prevents LPS-induced cardiac dysfunction via blockade of presynaptic alpha2A-adrenergic receptor.PLoS One8:e63622. 10.1371/journal.pone.0063622

  • CrossRef
  • Google Scholar

• 195

  WassermanA. J.HorganJ. H.Ul-HassanZ.ProctorJ. D. (1975). Diphenidol treatment of arrhythmias.Chest67422–424.

  • Google Scholar

• 196

  WeaverL. C.AlexanderW. M.AbreuB. E.RichardsA. B.JonesW. R.BegleyR. W. (1958). The mechanism of the hypotensive action of narcotine hydrochloride.J. Pharmacol. Exp. Ther.123287–295.

  • Google Scholar

• 197

  WolfleU.ElsholzF. A.KerstenA.HaarhausB.SchumacherU.SchemppC. M. (2016). Expression and functional activity of the human bitter taste receptor TAS2R38 in human placental tissues and JEG-3 Cells.Molecules21:306.

  • Google Scholar

• 198

  WolfleU.HaarhausB.KerstenA.FiebichB.HugM. J.SchemppC. M. (2015). Salicin from willow bark can modulate neurite outgrowth in human neuroblastoma SH-SY5Y cells. Phytother. Res.29, 1494–1500. 10.1002/ptr.5400

  • CrossRef
  • Google Scholar

• 199

  WoodD.WebsterE.MartinezD.DarganP.JonesA. (2002). Case report: survival after deliberate strychnine self-poisoning, with toxicokinetic data.Crit. Care6456–459.

  • Google Scholar

• 200

  WoodingS. P.AtanasovaS.GunnH. C.StanevaR.DimovaI.TonchevaD. (2012). Association of a bitter taste receptor mutation with Balkan Endemic Nephropathy (BEN).BMC Med. Genet.ics13:96.

  • Google Scholar

• 201

  WuT. C.ChaoC. Y.LinS. J.ChenJ. W. (2012). Low-dose dextromethorphan, a NADPH oxidase inhibitor, reduces blood pressure and enhances vascular protection in experimental hypertension.PLoS One7:e46067. 10.1371/journal.pone.0046067

  • CrossRef
  • Google Scholar

• 202

  YanW.SunavalaG.RosenzweigS.DassoM.BrandJ. G.SpielmanA. I. (2001). Bitter taste transduced by PLC-beta(2)-dependent rise in IP(3) and alpha-gustducin-dependent fall in cyclic nucleotides.Am. J. Physiol. Cell Physiol.280C742–C751.

  • Google Scholar

• 203

  YanY.HuY.NorthK. E.FranceschiniN.LinD. (2009). Evaluation of population impact of candidate polymorphisms for coronary heart disease in the Framingham Heart Study Offspring Cohort.BMC Proc.3(Suppl. 7):S118.

  • Google Scholar

• 204

  YangC. C.DengJ. F. (1998). Clinical experience in acute overdosage of diphenidol.J. Toxicol. Clin. Toxicol.3633–39.

  • Google Scholar

• 205

  YangP. C.KurokawaJ.FurukawaT.ClancyC. E. (2010). Acute effects of sex steroid hormones on susceptibility to cardiac arrhythmias: a simulation study.PLoS Comput. Biol.6:e1000658. 10.1371/journal.pcbi.1000658

  • CrossRef
  • Google Scholar

• 206

  YuJ. H.ChenD. Y.ChenH. Y.LeeK. H. (2016). Intravenous lipid-emulsion therapy in a patient with cardiac arrest after overdose of diphenhydramine.J. Formos. Med. Assoc.1151017–1018.

  • Google Scholar

• 207

  YucelA.OzyalcinS.TaluG. K.YucelE. C.ErdineS. (1999). Intravenous administration of caffeine sodium benzoate for postdural puncture headache.Reg. Anesth. Pain Med.2451–54.

  • Google Scholar

• 208

  ZengM.JiangW.TianY.HaoJ.CaoZ.LiuZ.et al (2017). Andrographolide inhibits arrhythmias and is cardioprotective in rabbits.Oncotarget861226–61238.

  • Google Scholar

• 209

  ZhangC.-H.LifshitzL. M.UyK. F.IkebeM.FogartyK. E.ZhugeR. (2013). The cellular and molecular basis of bitter tastant-induced bronchodilation.PLoS Biol.11:e1001501. 10.1371/journal.pbio.1001501

  • CrossRef
  • Google Scholar

• 210

  ZhangL.MaJ.LiS.XueR.JinM.ZhouY. (2015). Fatal diphenidol poisoning: a case report and a retrospective study of 16 cases.Forensic. Sci. Med. Pathol.11570–576.

  • Google Scholar

• 211

  ZhangX.BedigianA. V.WangW.EggertU. S. (2012). G-protein-coupled receptors participate in cytokinesis. Cytoskeleton (Hoboken)69, 810–818. 10.1002/cm.21055

  • CrossRef
  • Google Scholar

• 212

  ZhangY.HoonM. A.ChandrashekarJ.MuellerK. L.CookB.WuD.et al (2003). Coding of sweet, bitter, and umami tastes: different receptor cells sharing similar signaling pathways.Cell112293–301.

  • Google Scholar

• 213

  ZhengK.LuP.DelpapaE.BellveK.DengR.CondonJ. C.et al (2017). Bitter taste receptors as targets for tocolytics in preterm labor therapy. FASEB J.31, 4037–4052. 10.1096/fj.201601323RR

  • CrossRef
  • Google Scholar

• 214

  ZhengM.SimonR.MirlacherM.MaurerR.GasserT.ForsterT.et al (2004). TRIO amplification and abundant mRNA expression is associated with invasive tumor growth and rapid tumor cell proliferation in urinary bladder cancer.Am. J. Pathol.16563–69.

  • Google Scholar

• 215

  ZhouE.ParikhP. S.KanchugerM. S.BalsamL. B. (2019). Intraoperative anaphylaxis to chlorhexidine during LVAD and transplant surgery.J. Cardiothorac. Vasc. Anesth.33169–172.

  • Google Scholar

• 216

  ZhuK. J.HeF. T.JinN.LouJ. X.ChengH. (2009). Complete atrioventricular block associated with dapsone therapy: a rare complication of dapsone-induced hypersensitivity syndrome.J. Clin. Pharm. Ther.34489–492.

  • Google Scholar