Polycystin-1 Assembles With Kv Channels to Govern Cardiomyocyte Repolarization and Contractility

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.

SERCA overexpression reduces reperfusion-mediated cardiac microvascular damage through inhibition of the calcium/MCU/mPTP/necroptosis signaling pathways

“…Several studies have reported cardioprotective effects of SERCA [ 66 ]. For example, cardiomyocyte repolarization and contractility are handled by SERCA in cardiomyocytes through the Kv channels [ 67 ]. Diabetes-induced cardiac remodeling and cardiomyopathy are also linked to dysregulated SERCA in a manner dependent on the miR-133a [ 68 ].…”

Chronic activation of hexosamine biosynthesis in the heart triggers pathological cardiac remodeling

“…Adult cardiomyocytes were isolated from hearts of 8-16 weeks old male mice 57 . The isolated cells were plated in plating medium consisting of MEM, 2 mM L-glutamine, 1.26 mM CaCl 2 , 25 mM blebbistain, 1% penicillin/streptomycin, and 10% FBS.…”

Polycystin-1 Downregulation Induced Vascular Smooth Muscle Cells Phenotypic Alteration and Extracellular Matrix Remodeling in Thoracic Aortic Dissection

“…Notably, PC-1 is also involved in the pathogenesis of several cardiovascular diseases. The abated expression of PC-1 leads to the impaired contractility of cardiomyocytes via diminishing the calcium transients and sarcoplasmic reticulum calcium storage, consequently, resulting in cardiac dysfunction ( Balbo et al, 2016 ; Altamirano et al, 2019 ). Deficiency of PC-1 in endothelial cells also exhibited alterations in mechanosensitivity which further affected the flow-mediated vascular dilation ( Lorthioir et al, 2015 ).…”