Capel, Rebecca A, Bose, Samuel J, Collins, Thomas P, Rajasundaram, Skanda ORCID: 0009-0005-4447-3437, Ayagama, Thamali, Zaccolo, Manuela ORCID: 0000-0002-0934-3662, Burton, Rebecca-Ann Beatrice ORCID: 0000-0002-0904-3862 and Terrar, Derek A ORCID: 0000-0001-9408-6594
(2021)
IP<sub>3</sub>-mediated Ca<sup>2+</sup> release regulates atrial Ca<sup>2+</sup> transients and pacemaker function by stimulation of adenylyl cyclases.
American journal of physiology. Heart and circulatory physiology, 320 (1).
H95-H107.
Abstract
Inositol trisphosphate (IP<sub>3</sub>) is a Ca<sup>2+</sup>-mobilizing second messenger shown to modulate atrial muscle contraction and is thought to contribute to atrial fibrillation. Cellular pathways underlying IP<sub>3</sub> actions in cardiac tissue remain poorly understood, and the work presented here addresses the question whether IP<sub>3</sub>-mediated Ca<sup>2+</sup> release from the sarcoplasmic reticulum is linked to adenylyl cyclase activity including Ca<sup>2+</sup>-stimulated adenylyl cyclases (AC1 and AC8) that are selectively expressed in atria and sinoatrial node (SAN). Immunocytochemistry in guinea pig atrial myocytes identified colocalization of type 2 IP<sub>3</sub> receptors with AC8, while AC1 was located in close vicinity. Intracellular photorelease of IP<sub>3</sub> by UV light significantly enhanced the amplitude of the Ca<sup>2+</sup> transient (CaT) evoked by electrical stimulation of atrial myocytes (31 ± 6% increase 60 s after photorelease, <i>n</i> = 16). The increase in CaT amplitude was abolished by inhibitors of adenylyl cyclases (MDL-12,330) or protein kinase A (H89), showing that cAMP signaling is required for this effect of photoreleased IP<sub>3</sub>. In mouse, spontaneously beating right atrial preparations, phenylephrine, an α-adrenoceptor agonist with effects that depend on IP<sub>3</sub>-mediated Ca<sup>2+</sup> release, increased the maximum beating rate by 14.7 ± 0.5%, <i>n</i> = 10. This effect was substantially reduced by 2.5 µmol/L 2-aminoethyl diphenylborinate and abolished by a low dose of MDL-12,330, observations which are again consistent with a functional interaction between IP<sub>3</sub> and cAMP signaling involving Ca<sup>2+</sup> stimulation of adenylyl cyclases in the SAN pacemaker. Understanding the interaction between IP<sub>3</sub> receptor pathways and Ca<sup>2+</sup>-stimulated adenylyl cyclases provides important insights concerning acute mechanisms for initiation of atrial arrhythmias.<b>NEW & NOTEWORTHY</b> This study provides evidence supporting the proposal that IP<sub>3</sub> signaling in cardiac atria and sinoatrial node involves stimulation of Ca<sup>2+</sup>-activated adenylyl cyclases (AC1 and AC8) by IP<sub>3</sub>-evoked Ca<sup>2+</sup> release from junctional sarcoplasmic reticulum. AC8 and IP<sub>3</sub> receptors are shown to be located close together, while AC1 is nearby. Greater understanding of these novel aspects of the IP<sub>3</sub> signal transduction mechanism is important for future study in atrial physiology and pathophysiology, particularly atrial fibrillation.
Item Type: | Article |
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Uncontrolled Keywords: | Sarcoplasmic Reticulum, Heart Atria, Sinoatrial Node, Myocytes, Cardiac, Animals, Guinea Pigs, Mice, Inositol 1,4,5-Trisphosphate, Isoenzymes, Cyclic AMP-Dependent Protein Kinases, Calcium Signaling, Biological Clocks, Action Potentials, Heart Rate, Time Factors, Male, Inositol 1,4,5-Trisphosphate Receptors, Adenylyl Cyclases |
Divisions: | Faculty of Health and Life Sciences Faculty of Health and Life Sciences > Institute of Systems, Molecular and Integrative Biology |
Depositing User: | Symplectic Admin |
Date Deposited: | 09 Apr 2024 14:15 |
Last Modified: | 09 Apr 2024 15:41 |
DOI: | 10.1152/ajpheart.00380.2020 |
Open Access URL: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC78642... |
Related URLs: | |
URI: | https://livrepository.liverpool.ac.uk/id/eprint/3180245 |