Marianna Ranieri
Martin Schepelmann
Giovanna Valenti
Enikö Kallay
Daniela Riccardi- 1Department of Biosciences, Biotechnologies and Environment, University of Bari Aldo Moro, Bari, Italy
- 2Intitute for Pathophysiology and Allergy Research, Medical University of Vienna, Vienna, Austria
- 3School of Biosciences, Cardiff University, Cardiff, United Kingdom
Editorial on the Research Topic
The calcium-sensing receptor: from physiology to pharmacology
The Calcium-Sensing Receptor (CaSR) is a G protein-coupled receptor which is in many ways unique. Its best characterized role lies in mineral ion homeostasis via regulation of parathyroid hormone (PTH) secretion and calcium reabsorption in the kidneys (Riccardi and Valenti, 2016). In addition, the CaSR is involved in many other physiological processes, such as bone metabolism, neuronal differentiation, contraction and mineral ion homeostasis of/via smooth muscles, and renal water handling. Lastly, disturbances in CaSR expression or function lead to pathological conditions e.g., to inflammation in the airways and the gut, or pulmonary arterial hypertension (Yarova et al., 2015; Schepelmann et al., 2016; Hannan et al., 2018; Elajnaf et al., 2019; Ranieri et al., 2020; Schepelmann et al., 2021; Yarova et al., 2021; Schepelmann et al., 2022). This multiplicity of functions is achieved via ligand-biased signaling whereby CaSR ligands can evoke differential signaling pathways in a cell-specific manner. A fascinating recently identified feature of the CaSR is regulation of its protein expression levels via microRNA (Gong et al., 2012; Ranieri, 2019). The 6 reviews and research articles collected in this Research Topic summarize and expand on our current understanding of CaSR physiology and its linked pharmacological properties.
The role of the CaSR in inflammatory processes is currently of particular interest, as demonstrated by three of the articles in this Research Topic dealing with this subject. Iamartino and Brandi have reviewed several studies on the role of the CaSR in inducing and modulating pro-inflammatory stimuli in various organs and disease settings, namely, in immune cells, immune check-points, in the nervous system, specifically in the context of Alzheimer’s disease, in the respiratory, cardiovascular, and digestive systems, in adipose tissue, the kidneys, in the context of viral infection, etc. They also examined the possibility of treating such afflictions with negative allosteric CaSR modulators, calcilytics. Fittingly, Werner and Wagner have contributed an insightful review emphasizing CaSR-related effects on monocytes in rheumatoid arthritis. The authors propose that in this disease setting, calciprotein particles are formed due to a combination of increased local calcium concentrations and elevated fetuin-A levels. Together with increased extracellular Ca2+ levels and elevated levels of pro-inflammatory cytokines, these particles could lead to a “vicious cycle of inflammation and bone destruction” and targeting this vicious circle may provide a new therapeutic avenue against this disease. In an original research article, Gushchina et al. have shown that activation of the CaSR induces the PGE2 pathway in in vitro and in vivo models of colitis. Interestingly, the observed induction of PGE2 pathway-specific genes was different between the in vitro and in vivo settings. On the basis of this and previous results, the authors suggested that calcilytics may constitute a novel way of treating inflammatory bowel disease.
The other three articles of this Research Topic deal with specific features and action modes of the CaSR that highlight the versatility of this protein: in an elegant minireview, Centeno et al., described the role of extracellular phosphate and intracellular phosphorylation in inhibiting and modulating CaSR activity. They illustrate how extracellular phosphate modulates PTH secretion via CaSR inhibition. The authors lead through this topic via an explanation of the structure of the CaSR and its binding sites for various ligands and ions, and progress via a detailed account of what is known on the complex interaction of CaSR and extracellular phosphate as well as intracellular CaSR phosphorylation and CaSR activity. Intracellular phosphorylation of the CaSR is also a key feature of yet another non-calciotropic role of the CaSR, namely, that of a temperature sensor. In a pivotal study, Brennan et al. demonstrated that the C-terminal domain of the CaSR mediates its temperature-sensing capabilities. Changes in temperature directly influence CaSR induced intracellular Ca2+ oscillation frequency. The anterior preoptic nucleus, a key temperature sensing organ, expresses the CaSR. This organ has been linked to a genetic disorder of thermoregulation in patients with autosomal dominant hypocalcemia with hypercalciuria (ADH) type 1, a disease caused by activating mutations in the CaSR gene. As calcilytics are already being tested for the treatment of ADH, they might also prove beneficial in managing infantile febrile convulsions seen in some ADH children.
Finally, Lindner et al., investigated in a research article the CaSR-independent role of the positive allosteric CaSR modulator cinacalcet on voltage-gated sodium channels in neocortical neurons via a yet unknown GPCR other than the CaSR. Using electrophysiological approaches, the authors demonstrated that cinacalcet inhibits these channels and thus neuronal action potentials, especially when the channels are in their fast-inactivated state. The authors conclude that cinacalcet could serve as a template molecule for the development of a new class of sodium channel inhibitors. At the same time, due to its action on neuronal activity, cinacalcet may interact with brain function in patients treated with this drug.
To conclude, the up-to-date and state-of the-art understanding of CaSR pathophysiology presented in this Research Topic would be expected to lead to the identification of novel therapeutic strategies for treating a variety of conditions, including inflammatory diseases and thermoregulation.
Author contributions
MR, MS, GV, EK, and DR prepared the manuscript. All authors contributed to the article and approved the submitted version.
Funding
Funded by the Austrian Science Fund (FWF) and the Herzfelder’sche Familienstiftung, grant number P 32840-B (to MS); FWF, grant number P 29948-B28 (to EK); the European Union’s Horizon 2020 research and innovation programme, grant agreement number 675228 (to EK). MR is supported by POR Puglia 2014/2020—Asse X—Azione 10.4. Research for Innovation—REFIN (Code n. 4FC8E072).
Conflict of interest
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
Publisher’s note
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References
Elajnaf, T., Iamartino, L., Mesteri, I., Muller, C., Bassetto, M., Manhardt, T., et al. (2019). Nutritional and pharmacological targeting of the calcium-sensing receptor influences chemically induced colitis in mice. Nutrients 11 (12), 3072. doi:10.3390/nu11123072
Gong, Y., Renigunta, V., Himmerkus, N., Zhang, J., Renigunta, A., Bleich, M., et al. (2012). Claudin-14 regulates renal Ca⁺⁺ transport in response to CaSR signalling via a novel microRNA pathway. EMBO J. 31 (8), 1999–2012. doi:10.1038/emboj.2012.49
Hannan, F. M., Kallay, E., Chang, W., Brandi, M. L., and Thakker, R. V. (2018). The calcium-sensing receptor in physiology and in calcitropic and noncalcitropic diseases. Nat. Rev. Endocrinol. 15 (1), 33–51. doi:10.1038/s41574-018-0115-0
Ranieri, M., Di Mise, A., Tamma, G., and Valenti, G. (2020). Calcium sensing receptor exerts a negative regulatory action toward vasopressin-induced aquaporin-2 expression and trafficking in renal collecting duct. Vitam. Horm. 112, 289–310. doi:10.1016/bs.vh.2019.08.008
Ranieri, M. (2019). Renal Ca(2+) and water handling in response to calcium sensing receptor signaling: Physiopathological aspects and role of CaSR-regulated microRNAs. Int. J. Mol. Sci. 20 (21), 5341. doi:10.3390/ijms20215341
Riccardi, D., and Valenti, G. (2016). Localization and function of the renal calcium-sensing receptor. Nat. Rev. Nephrol. 12 (7), 414–425. doi:10.1038/nrneph.2016.59
Schepelmann, M., Kupper, N., Sladczyk, M., Mansfield, B., Manhardt, T., Piatek, K., et al. (2021). Stereo-specific modulation of the extracellular calcium-sensing receptor in colon cancer cells. Int. J. Mol. Sci. 22 (18), 10124. doi:10.3390/ijms221810124
Schepelmann, M., Ranieri, M., Lopez-Fernandez, I., Webberley, T. S., Brennan, S. C., Yarova, P. L., et al. (2022). Impaired mineral ion metabolism in a mouse model of targeted calcium-sensing receptor (CaSR) deletion from vascular smooth muscle cells. J. Am. Soc. Nephrol. 33 (7), 1323–1340. doi:10.1681/ASN.2021040585
Schepelmann, M., Yarova, P. L., Lopez-Fernandez, I., Davies, T. S., Brennan, S. C., Edwards, P. J., et al. (2016). The vascular Ca2+-sensing receptor regulates blood vessel tone and blood pressure. Am. J. Physiol. Cell. Physiol. 310 (3), C193–C204. doi:10.1152/ajpcell.00248.2015
Yarova, P. L., Huang, P., Schepelmann, M. W., Bruce, R., Ecker, R., Nica, R., et al. (2021). Characterization of negative allosteric modulators of the calcium-sensing receptor for repurposing as a treatment of asthma. J. Pharmacol. Exp. Ther. 376 (1), 51–63. doi:10.1124/jpet.120.000281
Keywords: calcium-sensing receptor (CaSR), therapeutic target, CaSR signalling, inflammation, monocytes, PGE2, VGSC, temperature sensing
Citation: Ranieri M, Schepelmann M, Valenti G, Kallay E and Riccardi D (2023) Editorial: The calcium-sensing receptor: from physiology to pharmacology. Front. Physiol. 14:1225074. doi: 10.3389/fphys.2023.1225074
Received: 18 May 2023; Accepted: 30 May 2023;
Published: 06 June 2023.
Edited and reviewed by:
Christoph Fahlke, Helmholtz Association of German Research Centres (HZ), GermanyCopyright © 2023 Ranieri, Schepelmann, Valenti, Kallay and Riccardi. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
*Correspondence: Marianna Ranieri, bWFyaWFubmEucmFuaWVyaUB1bmliYS5pdA==; Martin Schepelmann, bWFydGluLnNjaGVwZWxtYW5uQG1lZHVuaXdpZW4uYWMuYXQ=
†These authors have contributed equally to this work