Emerging Evidence for cAMP-calcium Cross Talk in Heart Atrial Nanodomains Where IP(3)-Evoked Calcium Release Stimulates Adenylyl Cyclases

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 (IP(3)) is a calcium-mobilizing second messenger and its agonist-induced effects have been observed in many tissue types. In the atria IP(3) receptors (IR(3)Rs) 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 IP(3) actions in atrial myocytes depends on stimulation of calcium-dependent forms of adenylyl cyclase (AC8 and AC1) by IP(3)-evoked calcium release from the sarcoplasmic reticulum. AC8 shows co-localisation with IP(3)Rs 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.