Polycystin-1 assembles with Kv channels to govern cardiomyocyte repolarization and contractility

Item Type:	Article
Title:	Polycystin-1 assembles with Kv channels to govern cardiomyocyte repolarization and contractility
Creators Name:	Altamirano, F. and Schiattarella, G.G. and French, K.M. and Kim, S.Y. and Engelberger, F. and Kyrychenko, S. and Villalobos, E. and Tong, D. and Schneider, J.W. and Ramirez-Sarmiento, C.A. and Lavandero, S. and Gillette, T.G. and Hill, J.A.
Abstract:	BACKGROUND: Polycystin-1 (PC1) is a transmembrane protein originally identified in autosomal dominant polycystic kidney disease where it regulates the calcium-permeant cation channel polycystin-2. Autosomal dominant polycystic kidney disease patients develop renal failure, hypertension, left ventricular hypertrophy, and diastolic dysfunction, among other cardiovascular disorders. These individuals harbor PC1 loss-of-function mutations in their cardiomyocytes, but the functional consequences are unknown. PC1 is ubiquitously expressed, and its experimental ablation in cardiomyocyte-specific knockout mice reduces contractile function. Here, we set out to determine the pathophysiological role of PC1 in cardiomyocytes. METHODS: Wild-type and cardiomyocyte-specific PC1 knockout mice were analyzed by echocardiography. Excitation-contraction coupling was assessed in isolated cardiomyocytes and human embryonic stem cell-derived cardiomyocytes, and functional consequences were explored in heterologous expression systems. Protein-protein interactions were analyzed biochemically and by means of ab initio calculations. RESULTS: PC1 ablation reduced action potential duration in cardiomyocytes, decreased Ca(2+) transients, and myocyte contractility. PC1-deficient cardiomyocytes manifested a reduction in sarcoendoplasmic reticulum Ca(2+) stores attributable to a reduced action potential duration and sarcoendoplasmic reticulum Ca(2+) ATPase (SERCA) activity. An increase in outward K(+) currents decreased action potential duration in cardiomyocytes lacking PC1. Overexpression of full-length PC1 in HEK293 cells significantly reduced the current density of heterologously expressed Kv4.3, Kv1.5 and Kv2.1 potassium channels. PC1 C terminus inhibited Kv4.3 currents to the same degree as full-length PC1. Additionally, PC1 coimmunoprecipitated with Kv4.3, and a modeled PC1 C-terminal structure suggested the existence of 2 docking sites for PC1 within the N terminus of Kv4.3, supporting a physical interaction. Finally, a naturally occurring human mutant PC1(R4228X) manifested no suppressive effects on Kv4.3 channel activity. CONCLUSIONS: Our findings uncover a role for PC1 in regulating multiple Kv channels, governing membrane repolarization and alterations in SERCA activity that reduce cardiomyocyte contractility.
Keywords:	Action Potential, Kv1.5 Potassium Channel, Kv2.1 Potassium Channel, Kv4.3 Potassium Channel, L-Type Calcium Channel, Ryanodine Receptor, Voltage-Gated Potassium Channel, Animals, Mice
Source:	Circulation
ISSN:	0009-7322
Publisher:	American Heart Association
Volume:	140
Number:	11
Page Range:	921-936
Date:	10 September 2019
Official Publication:	https://doi.org/10.1161/CIRCULATIONAHA.118.034731
PubMed:	View item in PubMed

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