CRBN degrades Cav1.2α to regulate cardiac dysfunction

Cereblon (CRBN) is a substrate receptor of the E3 ubiquitin ligase complex, which has been reported to target ion channel proteins. Modulation of the L-type voltage-dependent Ca2+ channel α1c subunit (Cav1.2α) is a critical player in heart failure associated with reduced ejection fraction (HFrEF), but the underlying cellular mechanisms are unclear. Here, we explored the role of CRBN in HFrEF by investigating the direct regulatory role of CRBN in Cav1.2α activity, and how it can serve as a target to address myocardial dysfunction. Cardiac tissues from HFrEF patients exhibit increased levels of CRBN, suggesting its involvement in heart failure (HF). In vivo and ex vivo animal model studies demonstrate that whole body CRBN-knockout (CRBN-/-) and cardiac-specific knockout mice (Crbnfl/fl/Myh6Cre+,) enhanced cardiac contractility with increased L-type calcium channel current (ICaL), modulated by the direct interaction of CRBN with Cav1.2α subunit. Mechanistically, we discovered that the Lon domain of CRBN directly interacts with the N-terminal of Cav1.2α. Increasing CRBN levels enhanced ubiquitination and proteasomal degradation of Cav1.2α and decreased L-type Ca2+ channel currents. By contrast, genetic or pharmacological depletion of CRBN via TD-165, a novel CRBN-targeting degrader, increased the surface expression of Cav1.2α and enhanced L-type Ca2+ channel currents. We have also discovered that CRBN-/- mice exhibited resistance to doxorubicin-induced HF. findings indicate that CRBN selectively degrades Cav1.2α, which in turn facilitates cardiac dysfunction, suggesting that reducing CRBN levels could serve as a new target of cardioprotective therapeutic strategy for HF.