POPDC1 scaffolds a complex of adenylyl cyclase 9 and the potassium channel TREK‐1 in heart. (18th October 2022)

• Record Type: Journal Article
• Authors: Baldwin, Tanya A; Li, Yong; Marsden, Autumn N; Rinné, Susanne; Garza‐Carbajal, Anibal; Schindler, Roland F R; Zhang, Musi; Garcia, Mia A; Venna, Venugopal Reddy; Decher, Niels; Brand, Thomas; Dessauer, Carmen W
• Is Part Of: EMBO reports. Volume 23:Number 12(2022)
• Page Start: n/a
• Page End: n/a
• Publication Date: 2022-10-18
• Subjects: ADCY9 -- adenylyl cyclase -- BVES -- heart rate variability -- TREK‐1; Molecular biology -- Periodicals; Molecular Biology -- Periodicals; Molecular biology; Periodicals; 572.8
• DOI: 10.15252/embr.202255208
• Languages: English
• ISSNs: 1469-221X

Abstract

Abstract: The establishment of macromolecular complexes by scaffolding proteins is key to the local production of cAMP by anchored adenylyl cyclase (AC) and the subsequent cAMP signaling necessary for cardiac functions. We identify a novel AC scaffold, the Popeye domain‐containing (POPDC) protein. The POPDC family of proteins is important for cardiac pacemaking and conduction, due in part to their cAMP‐dependent binding and regulation of TREK‐1 potassium channels. We show that TREK‐1 binds the AC9:POPDC1 complex and copurifies in a POPDC1‐dependent manner with AC9 activity in heart. Although the AC9:POPDC1 interaction is cAMP‐independent, TREK‐1 association with AC9 and POPDC1 is reduced upon stimulation of the β‐adrenergic receptor (βAR). AC9 activity is required for βAR reduction of TREK‐1 complex formation with AC9:POPDC1 and in reversing POPDC1 enhancement of TREK‐1 currents. Finally, deletion of the gene‐encoding AC9 ( Adcy9) gives rise to bradycardia at rest and stress‐induced heart rate variability, a milder phenotype than the loss of Popdc1 but similar to the loss of Kcnk2 (TREK‐1). Thus, POPDC1 represents a novel adaptor for AC9 interactions with TREK‐1 to regulate heart rate control. Synopsis: Adenylyl cyclase type 9 (AC9) regulates resting heart rate and binds the novel scaffolding protein POPDC1. The two‐pore potassium channel TREK‐1 is released in a cAMP‐dependent manner from a POPDC1:AC9 complex to regulate TREK‐1 potassium currents. The Popeye domain‐containing 1 (POPDC1) protein serves as a novel scaffold for adenylyl cyclase type 9 (AC9) that recruits the two‐pore potassium channel TREK‐1 in the absence of cAMP. Deletion of Adcy9 gives rise to a bradycardia at rest, heart rate variability during recovery from stress, and reduces the TREK‐1‐associated adenylyl cyclase activity in heart. Upon beta‐adrenergic stimulation of AC9, TREK‐1 association with AC9 and POPDC1 is reduced while interactions between AC9 and POPDC1 remain unchanged. AC9 activity within the POPDC1 complex controls the enhancement of TREK‐1 currents by POPDC1, representing a novel form of regulation for heart rate control. Abstract : Adenylyl cyclase type 9 (AC9) regulates resting heart rate and binds the novel scaffolding protein POPDC1. The two‐pore potassium channel TREK‐1 is released in a cAMP‐dependent manner from a POPDC1:AC9 complex to regulate TREK‐1 potassium currents.