cAMP signalling is required for the actions of IP ₃ on Ca ²⁺ -transients in cardiac atria and beating rate in sino-atrial node

Inositol trisphosphate (IP 3 ) is a major Ca 2+ -mobilising second messenger and atrial IP 3 receptor (IP 3 R) expression is greatly increased in atrial fibrillation (AF). Cardiac atrial and sino-atrial node (SAN) myocytes also express Ca 2+ -stimulated adenylyl cyclases (AC1 and AC8); however the pathways underlying atrial AC1 and AC8 activation are unknown. We investigated whether IP 3 signalling in cardiac atria and SAN utilises ACs. Immunocytochemistry in isolated guinea pig atrial myocytes identified co-localisation of type 2 IP 3 Rs with AC8, while AC1 was located in close vicinity. UV photorelease of IP 3 significantly enhanced Ca 2+ 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 μmol/L 2-APB and abolished by a low dose of MDL-12,330. These observations are consistent with a functional interaction between IP 3 and cAMP signalling involving Ca 2+ 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.