IP-mediated Ca Release Regulates Atrial Ca Transients and Pacemaker Function by Stimulation of Adenylyl Cyclases

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