IP₃-mediated Ca²⁺ release regulates atrial Ca²⁺ transients and pacemaker function by stimulation of adenylyl cyclases

Inositol trisphosphate (IP₃) is a Ca²⁺-mobilizing second messenger shown to modulate atrial muscle contraction and is thought to contribute to atrial fibrillation. Cellular pathways underlying IP₃ actions in cardiac tissue remain poorly understood, and the work presented here addresses the question whether IP₃-mediated Ca²⁺ release from the sarcoplasmic reticulum is linked to adenylyl cyclase activity including Ca²⁺-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 IP₃ receptors with AC8, while AC1 was located in close vicinity. Intracellular photorelease of IP₃ by UV light significantly enhanced the amplitude of the Ca²⁺ transient (CaT) evoked by electrical stimulation of atrial myocytes (31 ± 6% increase 60 s after photorelease, n = 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 IP₃. In mouse, spontaneously beating right atrial preparations, phenylephrine, an α-adrenoceptor agonist with effects that depend on IP₃-mediated Ca²⁺ release, increased the maximum beating rate by 14.7 ± 0.5%, n = 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 IP₃ and cAMP signaling involving Ca²⁺ stimulation of adenylyl cyclases in the SAN pacemaker. Understanding the interaction between IP₃ receptor pathways and Ca²⁺-stimulated adenylyl cyclases provides important insights concerning acute mechanisms for initiation of atrial arrhythmias.NEW & NOTEWORTHY This study provides evidence supporting the proposal that IP₃ signaling in cardiac atria and sinoatrial node involves stimulation of Ca²⁺-activated adenylyl cyclases (AC1 and AC8) by IP₃-evoked Ca²⁺ release from junctional sarcoplasmic reticulum. AC8 and IP₃ receptors are shown to be located close together, while AC1 is nearby. Greater understanding of these novel aspects of the IP₃ signal transduction mechanism is important for future study in atrial physiology and pathophysiology, particularly atrial fibrillation.