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

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.

Inhibition of adenylyl cyclase 1 by ST034307 inhibits IP3-evoked changes in sino-atrial node beat rate

“…These patterns of expression appear to coincide with our own observations for expression in guinea pig atrial and SAN cells ( Figure 2 ). Previous work has suggested that AC1 might be located close to but not at the surface membrane, though still within reach of Ca 2+ released via IP 3 R ( Collins and Terrar, 2012 ; and see Burton and Terrar, 2021 ). Higher resolution EM work will be required in the future to provide more information on the precise location of AC1.…”

“…Under normal physiological conditions, both cardiac ECC and pacemaker activity are primarily regulated via β-adrenergic and muscarinic signalling, leading to downstream activation of adenylyl cyclase, predominantly AC5 and AC6 ( Katsushika et al, 1992 ; Premont et al, 1992 ), and subsequent generation of cyclic-adenosine monophosphate (cAMP) ( Bers, 2002 ; Burton and Terrar 2021 ). In ventricular cardiomyocytes, IP 3 receptors (IP 3 R) are largely confined to the nuclear envelope and IP 3 signalling is not thought to play a major role in cellular Ca 2+ handling ( Nakayama et al, 2010 ; Tinker et al, 2016 ).…”

“…Indeed, it appears this coupling is essential for pacemaker function in human SAN cells ( Tsutsui et al, 2018 ). Membrane clock activity results from the alternation and balance between depolarising currents (e.g., I f , I CaL , I sust ) and repolarising currents (e.g., I Ks and I Kr ) ( Difrancesco and Tromba, 1988 ; Difrancesco et al, 1991 ; Burton and Terrar, 2021 ). I f is carried by the HCN channels and modulated by changes in cytosolic Ca 2+ ( Rigg et al, 2003 ), as well as sub-sarcolemmal cAMP ( Difrancesco and Tortora, 1991 ; Burton and Terrar, 2021 ).…”

“…Membrane clock activity results from the alternation and balance between depolarising currents (e.g., I f , I CaL , I sust ) and repolarising currents (e.g., I Ks and I Kr ) ( Difrancesco and Tromba, 1988 ; Difrancesco et al, 1991 ; Burton and Terrar, 2021 ). I f is carried by the HCN channels and modulated by changes in cytosolic Ca 2+ ( Rigg et al, 2003 ), as well as sub-sarcolemmal cAMP ( Difrancesco and Tortora, 1991 ; Burton and Terrar, 2021 ). I f , and therefore SAN pacemaking, can thereby be influenced by phosphodiesterase (PDE) and AC activity ( Difrancesco and Tortora, 1991 ; Mattick et al, 2007 ; Vinogradova et al, 2008 ).…”

“…Although a more modest component, ECC in the atria and sino-atrial node (SAN) is also regulated by α-adrenergic signalling (Lipp et al, 2000;Mackenzie et al, 2002;Capel et al, 2021). In addition to the regulation of ECC, currents that contribute to the pacemaker potential in the SAN and atrioventricular node (AVN) are also highly dependent on the regulation of intracellular Ca 2+ signalling (Hancox and Mitcheson, 1997;Lakatta et al, 2010;Capel and Terrar, 2015;Burton and Terrar, 2021). In nodal cells, the pacemaker potential is dependent upon diastolic depolarisation, in part due to the influence of the hyperpolarisation activated "funny" current I f and local calcium release events from the sarcoplasmic reticulum (SR).…”