The Cavβ subunit prevents RFP2-mediated ubiquitination and proteasomal degradation of L-type channels

It is well established that the auxiliary Cav beta subunit regulates calcium channel density in the plasma membrane, but the cellular mechanism by which this occurs has remained unclear. We found that the Cav beta subunit increased membrane expression of Cav1.2 channels by preventing the entry of the channels into the endoplasmic reticulum-associated protein degradation (ERAD) complex. Without Cav beta, Cav1.2 channels underwent robust ubiquitination by the RFP2 ubiquitin ligase and interacted with the ERAD complex proteins derlin-1 and p97, culminating in targeting of the channels to the proteasome for degradation. On treatment with the proteasomal inhibitor MG132, Cav beta-free channels were rescued from degradation and trafficked to the plasma membrane. The coexpression of Cav beta interfered with ubiquitination and targeting of the channel to the ERAD complex, thereby facilitating export from the endoplasmic reticulum and promoting expression on the cell surface. Thus, Cav beta regulates the ubiquitination and stability of the calcium channel complex.