Cereblon-mediated TRPC1 degradation regulates Ca2+ influx in the heart

Abstract

•This study investigated how cereblon (CRBN), a substrate receptor of the E3 ubiquitin ligase complex that selectively degrades ion channels, targets cardiac transient receptor potential channel 1 (TRPC1).•Physiologically, CRBN ablation upregulated TRPC1 expression.•Mechanistically, the CRBN Lon domain directly interacts with the C- and N-terminals of TRPC1.•Increasing CRBN levels enhanced TRPC1 ubiquitination and proteasomal degradation.•TRPC1 overexpression in HEK293-CRBN KO cells enhanced TRPC1 current density and Ca2+ transients.•Pathologically, cardiac TRPC1 expression in CRBN-deficient mice was increased during ex vivo ischemic/reperfusion.•Targeting the CRBN-TRPC1 axis may serve as a novel therapeutic approach to address cardiac disease.