AUTHOR=Hohendanner Felix , McCulloch Andrew D., Blatter Lothar A., Michailova Anushka P. TITLE=Calcium and IP3 dynamics in cardiac myocytes: experimental and computational perspectives and approaches JOURNAL=Frontiers in Pharmacology VOLUME=5 YEAR=2014 URL=https://www.frontiersin.org/journals/pharmacology/articles/10.3389/fphar.2014.00035 DOI=10.3389/fphar.2014.00035 ISSN=1663-9812 ABSTRACT=

Calcium plays a crucial role in excitation-contraction coupling (ECC), but it is also a pivotal second messenger activating Ca²⁺-dependent transcription factors in a process termed excitation-transcription coupling (ETC). Evidence accumulated over the past decade indicates a pivotal role of inositol 1,4,5-trisphosphate receptor (IP₃R)-mediated Ca²⁺ release in the regulation of cytosolic and nuclear Ca²⁺ signals. IP₃ is generated by stimulation of plasma membrane receptors that couple to phospholipase C (PLC), liberating IP₃ from phosphatidylinositol 4,5-bisphosphate (PIP₂). An intriguing aspect of IP₃ signaling is the presence of the entire PIP₂-PLC-IP₃ signaling cascade as well as the presence of IP₃Rs at the inner and outer membranes of the nuclear envelope (NE) which functions as a Ca²⁺ store. The observation that the nucleus is surrounded by its own putative Ca²⁺ store raises the possibility that nuclear IP₃-dependent Ca²⁺ release plays a critical role in ETC. This provides a potential mechanism of regulation that acts locally and autonomously from the global cytosolic Ca²⁺ signal underlying ECC. Moreover, there is evidence that: (i) the sarcoplasmic reticulum (SR) and NE are a single contiguous Ca²⁺ store; (ii) the nuclear pore complex is the major gateway for Ca²⁺ and macromolecules to pass between the cytosol and the nucleoplasm; (iii) the inner membrane of the NE hosts key Ca²⁺ handling proteins including the Na⁺/Ca²⁺ exchanger (NCX)/GM1 complex, ryanodine receptors (RyRs), nicotinic acid adenine dinucleotide phosphate receptors (NAADPRs), Na⁺/K⁺ ATPase, and Na⁺/H⁺ exchanger. Thus, it appears that the nucleus represents a Ca²⁺ signaling domain equipped with its own ion channels and transporters that allow for complex local Ca²⁺ signals. Many experimental and modeling approaches have been used for the study of intracellular Ca²⁺ signaling but the key to the understanding of the dual role of Ca²⁺ mediating ECC and ECT lays in quantitative differences of local [Ca²⁺] in the nuclear and cytosolic compartment. In this review, we discuss the state of knowledge regarding the origin and the physiological implications of nuclear Ca²⁺ transients in different cardiac cell types (adult atrial and ventricular myocytes) as well as experimental and mathematical approaches to study Ca²⁺ and IP₃ signaling in the cytosol and nucleus. In particular, we focus on the concept that highly localized Ca²⁺ signals are required to translocate and activate Ca²⁺-dependent transcription factors (e.g., nuclear factor of activated T-cells, NFAT; histone deacetylase, HDAC) through phosphorylation/dephosphorylation processes.