Cereblon contributes to cardiac dysfunction by degrading Cav1.2α

Abstract

Aims Cereblon (CRBN) is a substrate receptor of the E3 ubiquitin ligase complex that was reported to target ion channel proteins. L-type voltage-dependent Ca2+ channel (LTCC) density and dysfunction is a critical player in heart failure with reduced ejection fraction (HFrEF). However, the underlying cellular mechanisms by which CRBN regulates LTCC subtype Cav1.2α during cardiac dysfunction remain unclear. Here, we explored the role of CRBN in HFrEF by investigating the direct regulatory role of CRBN in Cav1.2α activity and examining how it can serve as a target to address myocardial dysfunction. Methods and results Cardiac tissues from HFrEF patients exhibited increased levels of CRBN compared with controls. In vivo and ex vivo studies demonstrated that whole-body CRBN knockout (CRBN−/−) and cardiac-specific knockout mice (Crbnfl/fl/Myh6Cre+) exhibited enhanced cardiac contractility with increased LTCC current (ICaL) compared with their respective controls, which was modulated by the direct interaction of CRBN with Cav1.2α. Mechanistically, the Lon domain of CRBN directly interacted with the N-terminal of Cav1.2α. Increasing CRBN levels enhanced the ubiquitination and proteasomal degradation of Cav1.2α and decreased ICaL. In contrast, genetic or pharmacological depletion of CRBN via TD-165, a novel PROTAC-based CRBN degrader, increased surface expression of Cav1.2α and enhanced ICaL. Low CRBN levels protected the heart against cardiomyopathy in vivo. Conclusion Cereblon selectively degrades Cav1.2α, which in turn facilitates cardiac dysfunction. A targeted approach or an efficient method of reducing CRBN levels could serve as a promising strategy for HFrEF therapeutics. Key question Key finding Take-home message Cereblon modulates cardiac function by altering Cav1.2α current density and CRBN-targeting therapy could serve as a novel strategy for future HFrEF therapeutics.

The CB1receptor interacts with cereblon and drives cereblon deficiency-associated memory shortfalls

“…Our findings may therefore help to reconcile these inconsistencies as CB 1 Rs reduce glutamate release (Piomelli, 2003) and may also activate BK Ca channels under certain conditions (Stumpff et al, 2005;Romano & Lograno, 2006;López-Dyck et al, 2017). Furthermore, CRBN-KO mice show a resilient phenotype towards stress (Akber et al, 2022;Park et al, 2022). and the pathological aggregation of Tau, a hallmark of tauopathies as Alzheimer's disease (Akber et al, 2021).…”

The CB1 receptor interacts with cereblon and drives cereblon deficiency-associated memory shortfalls

“…Our findings may therefore help to reconcile these inconsistencies as CB 1 Rs reduce glutamate release (Piomelli, 2003 ) and may also activate BK Ca channels under certain conditions (Stumpff et al, 2005 ; Romano and Lograno, 2006 ; López-Dyck et al, 2017 ). Furthermore, CRBN-KO mice show a resilient phenotype towards stress (Akber et al, 2022 ; Park et al, 2022 ) and the pathological aggregation of Tau, a hallmark of tauopathies as Alzheimer’s disease (Akber et al, 2021 ). Facilitation of CB 1 R signalling also protects against acute and chronic stress, and chronic stress consistently downregulates CB 1 R (Morena et al, 2016 ).…”

Calcium Handling Remodeling Underlies Impaired Sympathetic Stress Response in Ventricular Myocardium from Cacna1c Haploinsufficient Rats

“…Our present results do not provide an answer to this question, and we can only speculate on the underlying cellular mechanisms. Cav1.2 expression, location, and function are regulated in a complex fashion by auxiliary subunits, regulatory proteins (such as RAD), phosphorylation events (e.g., by PKA), membrane trafficking, turnover or degradation of the channel, e.g., [ 2 , 21 , 22 , 23 ]. Potentially, alterations in some of these regulation processes may have led to an unaltered membrane density of Cav1.2 in Cacna1c +/− myocytes despite reduced global expression.…”