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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 sino-atrial node (SAN). Immunocytochemistry in guinea pig atrial myocytes identified co-localization of type 2 IP3Rs 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 post 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-APB 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.

Original publication

DOI

10.1152/ajpheart.00380.2020

Type

Journal article

Journal

American journal of physiology. Heart and circulatory physiology

Publication Date

16/10/2020

Keywords

adenylyl cyclase, Inositol trisphosphate, cyclic AMP, cardiac atria, Ca2+ signalling