Key result
Deletion of adenylyl cyclase 9 (AC9) in mice results in resting bradycardia and stress-induced heart rate variability, mediated by the POPDC1 scaffolding of AC9 and the TREK-1 potassium channel.
POPDC1 acts as a novel scaffolding protein for adenylyl cyclase 9 (AC9) to regulate the TREK-1 potassium channel, providing a molecular mechanism for resting heart rate control and stress-induced heart rate variability.
The establishment of macromolecular complexes by scaffolding proteins such as A-kinase anchoring proteins is key to the local production of cAMP by anchored adenylyl cyclase (AC) and the subsequent cAMP signaling necessary for many cardiac functions. We have identified herein a novel AC scaffold, the Popeye domain-containing (POPDC) protein. Unlike other AC scaffolding proteins, POPDC1 binds cAMP with high affinity. The POPDC family of proteins are important for cardiac pacemaking and conduction, due in part to their cAMP-dependent binding and regulation of TREK-1 potassium channels. TREK-1 binds the AC9:POPDC1 complex and co-purifies in a POPDC1-dependent manner with AC9-associated activity in heart. Although the interaction of AC9 and POPDC1 is cAMP independent, TREK-1 association with AC9 and POPDC1 is reduced in an isoproterenol-dependent manner, requiring an intact cAMP binding Popeye domain and AC activity within the complex. We show that deletion of Adcy9 (AC9) gives rise to bradycardia at rest and stress-induced heart rate variability. The phenotype for deletion of Adcy9 is milder than previously observed upon loss of Popdc1 , but similar to loss of Kcnk2 (TREK-1). Thus, POPDC1 represents a novel scaffolding protein for AC9 to regulate heart rate control. ONE-SENTENCE SUMMARY Adenylyl cyclase type 9 binds in an isoproterenol-dependent manner to the POPDC1:TREK-1 complex regulating heart rate.
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Baldwin et al. (2021) studied Heart rate variability and bradycardia (n=20). Adcy9 deletion vs. Wild-type was evaluated on Heart rate and heart rate variability. Deletion of adenylyl cyclase 9 (AC9) in mice results in resting bradycardia and stress-induced heart rate variability, mediated by the POPDC1 scaffolding of AC9 and the TREK-1 potassium channel.
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