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.
Highlights
IP3 signaling in the cytosol and nucleus
In this review we discussed the current state of experimental and modeling approaches to investigate nuclear and cytosolic Ca2+ homeostasis, whereby we focused on IP3-dependent Ca2+ signaling in adult myocytes
We presented experimental data from ventricular and atrial cells, showing the effects of sudden increases in [IP3] on nuclear and cytosolic Ca2+ transients during field stimulation as well as different approaches to study IP3-mediated Ca2+ release (i.e., FIRE-1-cyt as a tool to quantify [IP3], IP3 uncaging to mimic physiological increases in [IP3] and 2-Aminoethoxydiphenyl borate (2-APB) to block IP3R mediated Ca2+ release)
Summary
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. The neurohumoral stimulation with Endothelin I or Angiotensin II, has been shown to have similar positive inotropic effects in both ventricular and atrial cells, indicating a role of IP3-mediated Ca2+ release in the enhancement of cytosolic Ca2+ release
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