The N terminus-mediated Regulatory Role of Type VI adenylyl Cyclase (AC6) in the Heart

The type VI adenylyl cyclase (AC6), one of the nine different isotypes of membrane-bound adenylyl cyclases (ACs), is known to produce beneficial effects on failing hearts. AC6 is a major AC isoform in the heart and is coupled with the beta1 adrenergic receptor. Activation of ACs produces cAMP to activate PKA, which regulates intracellular Ca2+ handling proteins including the L-type Ca2+ channel, ryanodine receptor, and phospholamban. While AC6 provides the protective effect in the heart, another major cardiac AC isoform (AC5) showed detrimental effects during heart failure. This is intriguing because AC6 and AC5 are very similar in their protein sequences, except in their N terminuses. We therefore reason that the N-terminus of AC6 may play a critical role in controlling its function in the heart. To test this hypothesis, we created an AC6 N-terminus deleted mice (AC6△N, deletion of 2~86 amino acids of AC6). The basal cardiac functions and the stress response (isoproterenol, ISO; 10 mg/kg) were performed ...