Functional cyclic AMP signalling is required for the actions of IP3 on the Ca2+ transient in cardiac atria and beating rate in sino-atrial node

Inositol trisphosphate (IP3) is a major Ca2+-mobilising second messenger and atrial IP3 receptor (IP3R) expression is greatly increased in atrial fibrillation (AF). Cardiac atrial and sino-atrial node (SAN) myocytes also express Ca2+-stimulated adenylyl cyclases (AC1 and AC8); however the pathways underlying atrial AC1 and AC8 activation are unknown. We investigated whether IP3 signalling in cardiac atria and SAN utilises ACs. Immunocytochemistry in isolated guinea pig atrial myocytes identified co-localisation of type 2 IP3Rs with AC8, while AC1 was located in close vicinity. UV photorelease of IP3 significantly enhanced Ca2+ transient amplitudes following stimulation of atrial myocytes (31 {+/-} 6 % increase 60 s post photorelease, n=16), an effect abolished by inhibitors of ACs (MDL-12,330) or PKA (H89). The maximum rate change observed in spontaneously-beating murine right atrial preparations exposed to phenylephrine (14.7 {+/-} 0.5 %, n=10) was significantly reduced by 2.5 mol/L 2-APB and abolished by a low dose of MDL-12,330. These observations are consistent with a functional interaction between IP3 and cAMP signalling involving Ca2+ stimulation of ACs in cardiac atria and the SAN. Structural evidence supports AC8 as the most likely effector. This signal transduction mechanism is important for future study in atrial physiology and pathophysiology, particularly AF.