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...

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Bibliographic Details
Published in:American journal of physiology. Heart and circulatory physiology 2021-01, Vol.320 (1), p.H95-H107
Main Authors: Capel, Rebecca A, Bose, Samuel J, Collins, Thomas P, Rajasundaram, Skanda, Ayagama, Thamali, Zaccolo, Manuela, Burton, Rebecca-Ann Beatrice, Terrar, Derek A
Format: Article
Language:English
Subjects:
Adenylate cyclase
Adrenergic receptors
Amplitudes
Atria
Calcium (reticular)
Calcium ions
Calcium signalling
Cardiac muscle
Cyclic AMP
Electrical stimuli
Fibrillation
Guinea pigs
Immunocytochemistry
Inositol 1,4,5-trisphosphate receptors
Kinases
Muscle contraction
Muscles
Muscular function
Myocytes
Pacemakers
Phenylephrine
Protein kinase A
Receptors
Sarcoplasmic reticulum
Signal transduction
Signaling
Stimulation
Surgical implants
Ultraviolet radiation
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Summary: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
ISSN:0363-6135
1522-1539
DOI:10.1152/ajpheart.00380.2020