Emerging Evidence for cAMP-calcium Cross Talk in Heart Atrial Nanodomains Where IP3-Evoked Calcium Release Stimulates Adenylyl Cyclases.

Rebecca-Ann B Burton,Derek A Terrar

doi:10.1177/25152564211008341

Abstract

Calcium handling is vital to normal physiological function in the heart. Human atrial arrhythmias, eg. atrial fibrillation, are a major morbidity and mortality burden, yet major gaps remain in our understanding of how calcium signaling pathways function and interact. Inositol trisphosphate (IP3) is a calcium-mobilizing second messenger and its agonist-induced effects have been observed in many tissue types. In the atria IP3 receptors (IR3Rs) residing on junctional sarcoplasmic reticulum augment cellular calcium transients and, when over-stimulated, lead to arrhythmogenesis. Recent studies have demonstrated that the predominant pathway for IP3 actions in atrial myocytes depends on stimulation of calcium-dependent forms of adenylyl cyclase (AC8 and AC1) by IP3-evoked calcium release from the sarcoplasmic reticulum. AC8 shows co-localisation with IP3Rs and AC1 appears to be nearby. These observations support crosstalk between calcium and cAMP pathways in nanodomains in atria. Similar mechanisms also appear to operate in the pacemaker region of the sinoatrial node. Here we discuss these significant advances in our understanding of atrial physiology and pathology, together with implications for the identification of potential novel targets and modulators for the treatment of atrial arrhythmias.

Highlights

Calcium signaling is a key contributor to the normal physiological functioning of the heart
In the heart this process depends on calcium entry via calcium channels in the sarcolemmal membrane leading to release of additional calcium from the sarcoplasmic reticulum (SR) in a process described as calcium-induced-calcium-release (CICR)
The above discussion highlights and sets in context the recent observations showing interactions between cAMP and calcium signaling mechanisms in which cross talk between these pathways occurs in heart atrial nanodomains as a consequence of stimulation of calcium-activated adenylyl cyclases (AC8 and AC1) by IP3-evoked calcium release from the SR. These interacting signaling pathways lead to increases in the amplitude of calcium transients (CaTs) triggered by action potentials, and AC8 and AC1 enzymes stimulated by IP3-evoked calcium release are thought to be important newly identified components of mechanisms underlying atrial fibrillation

Summary

Introduction

Calcium signaling is a key contributor to the normal physiological functioning of the heart. Following on from the observations in atrial myocytes discussed above, it has been shown that the calcium stimulated adenylyl cyclases, AC8 and AC1, seem to be important players in mediating the chronotropic effects of IP3 in pacemaker cells (Capel et al, 2021).

Results

Conclusion