title: Aberrant Splicing Promotes Proteasomal Degradation of L-type CaV1.2 Calcium Channels by Competitive Binding for CaVβ Subunits in Cardiac Hypertrophy.
abstract: Decreased expression and activity of CaV1.2 calcium channels has been reported in pressure overload-induced cardiac hypertrophy and heart failure. However, the underlying mechanisms remain unknown. Here we identified in rodents a splice variant of CaV1.2 channel, named CaV1.2e21+22, that contained the pair of mutually exclusive exons 21 and 22. This variant was highly expressed in neonatal hearts. The abundance of this variant was gradually increased by 12.5-folds within 14 days of transverse aortic banding that induced cardiac hypertrophy in adult mouse hearts and was also elevated in left ventricles from patients with dilated cardiomyopathy. Although this variant did not conduct Ca2+ions, it reduced the cell-surface expression of wild-type CaV1.2 channels and consequently decreased the whole-cell Ca2+influx via the CaV1.2 channels. In addition, the CaV1.2e21+22variant interacted with CaVβ subunits significantly more than wild-type CaV1.2 channels, and competition of CaVβ subunits by CaV1.2e21+22consequently enhanced ubiquitination and subsequent proteasomal degradation of the wild-type CaV1.2 channels. Our findings show that the resurgence of a specific neonatal splice variant of CaV1.2 channels in adult heart under stress may contribute to heart failure.
authors.affiliation: Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore 117597, Singapore.
authors.forename: Zhenyu
authors.initials: Z
authors.lastname: Hu
authors.affiliation: Department of Surgery, Yong Loo Lin School of Medicine, National University of Singapore, 117597, Singapore.|Cardiovascular Research Institute, National University Health Systems, Centre for Translational Medicine, 117599, Singapore.
authors.forename: Jiong-Wei
authors.initials: JW
authors.lastname: Wang
authors.affiliation: Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore 117597, Singapore.
authors.forename: Dejie
authors.initials: D
authors.lastname: Yu
authors.affiliation: National Heart Centre Singapore, 5 hospital drive, 169609, Singapore.
authors.forename: Jia Lin
authors.initials: JL
authors.lastname: Soon
authors.affiliation: Department of Surgery, Yong Loo Lin School of Medicine, National University of Singapore, 117597, Singapore.|Cardiovascular Research Institute, National University Health Systems, Centre for Translational Medicine, 117599, Singapore.|Dept of Cardiology, University Medical Center Utrecht, 3584CX Utrecht, The Netherlands.
authors.forename: Dominique P V
authors.initials: DP
authors.lastname: de Kleijn
authors.affiliation: Cardiovascular Research Institute, National University Health Systems, Centre for Translational Medicine, 117599, Singapore.
authors.forename: Roger
authors.initials: R
authors.lastname: Foo
authors.affiliation: Calcium Signaling Laboratory, National Neuroscience Institute, 11 Jalan Tan Tock Seng 308433, Singapore.
authors.forename: Ping
authors.initials: P
authors.lastname: Liao
authors.affiliation: Department of Physiology and Cellular Biophysics, Columbia University, College of Physicians and Surgeons, New York, NY 10032, USA.
authors.forename: Henry M
authors.initials: HM
authors.lastname: Colecraft
authors.affiliation: Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore 117597, Singapore.|NUS Graduate School for Integrative Sciences and Engineering, 117456, Singapore.|Neurobiology/Ageing Programme, National University of Singapore, 117456, Singapore.
authors.forename: Tuck Wah
authors.initials: TW
authors.lastname: Soong
mesh_terms: D017398:Alternative Splicing; D000818:Animals; D001667:Binding, Competitive; D020746:Calcium Channels, L-Type / Q000235:genetics / Q000378:metabolism*; D006332:Cardiomegaly / Q000378:metabolism*; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism*; D059748:Proteolysis; D012326:RNA Splicing; D051381:Rats
chemical_list: D020746:Calcium Channels, L-Type; C419385:L-type calcium channel alpha(1C); D046988:Proteasome Endopeptidase Complex