title: The Cavβ subunit prevents RFP2-mediated ubiquitination and proteasomal degradation of L-type channels.
abstract: It is well established that the auxiliary Cavβ subunit regulates calcium channel density in the plasma membrane, but the cellular mechanism by which this occurs has remained unclear. We found that the Cavβ 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 Cavβ, 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, Cavβ-free channels were rescued from degradation and trafficked to the plasma membrane. The coexpression of Cavβ 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, Cavββ regulates the ubiquitination and stability of the calcium channel complex.
authors.affiliation: Department of Physiology and Pharmacology, Hotchkiss Brain Institute, University of Calgary, Calgary, Alberta, Canada.
authors.forename: Christophe
authors.initials: C
authors.lastname: Altier
authors.forename: Agustin
authors.initials: A
authors.lastname: Garcia-Caballero
authors.forename: Brett
authors.initials: B
authors.lastname: Simms
authors.forename: Haitao
authors.initials: H
authors.lastname: You
authors.forename: Lina
authors.initials: L
authors.lastname: Chen
authors.forename: Jan
authors.initials: J
authors.lastname: Walcher
authors.forename: H William
authors.initials: HW
authors.lastname: Tedford
authors.forename: Tamara
authors.initials: T
authors.lastname: Hermosilla
authors.forename: Gerald W
authors.initials: GW
authors.lastname: Zamponi
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D015153:Blotting, Western; D020746:Calcium Channels, L-Type / Q000235:genetics / Q000378:metabolism*; D002478:Cells, Cultured; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D004721:Endoplasmic Reticulum / Q000235:genetics / Q000378:metabolism*; D004797:Enzyme-Linked Immunosorbent Assay; D006624:Hippocampus / Q000166:cytology / Q000378:metabolism; D007150:Immunohistochemistry; D047468:Immunoprecipitation; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D018613:Microscopy, Confocal; D009474:Neurons / Q000166:cytology / Q000378:metabolism*; D046988:Proteasome Endopeptidase Complex / Q000235:genetics / Q000378:metabolism*; D021122:Protein Subunits / Q000235:genetics / Q000378:metabolism*; D051381:Rats; D047992:TNF Receptor-Associated Factor 2; D014162:Transfection; D047988:Tumor Necrosis Factor Receptor-Associated Peptides and Proteins / Q000235:genetics / Q000378:metabolism; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism*; D025801:Ubiquitin / Q000235:genetics / Q000378:metabolism; D054875:Ubiquitination / Q000502:physiology*
chemical_list: D020746:Calcium Channels, L-Type; D004268:DNA-Binding Proteins; C419385:L-type calcium channel alpha(1C); D008565:Membrane Proteins; C101338:PSMD2 protein, human; D021122:Protein Subunits; D047992:TNF Receptor-Associated Factor 2; C112217:TRIM13 protein, human; D047988:Tumor Necrosis Factor Receptor-Associated Peptides and Proteins; D025521:Tumor Suppressor Proteins; D025801:Ubiquitin; C530424:derlin-1 protein, mouse; D046988:Proteasome Endopeptidase Complex