Please use this identifier to cite or link to this item:
Title: Exclusion of alternative exon 33 of Ca<inf>V</inf>1.2 calcium channels in heart is proarrhythmogenic
Authors: Lia, G
Wang, J 
Liao, P 
Bartels, P
Zhang, H 
Yu, D 
Liang, MC 
Poh, KK 
Yu, CY 
Jiang, F 
Yong, TF 
Wong, YP 
Hu, Z 
Huang, H 
Zhang, G
Galupo, MJ
Bian, JS
Ponniah, S 
Trasti, SL
See, K
Foo, R 
Hoppe, UC
Herzig, S
Soong, TW 
Issue Date: 23-May-2017
Citation: Lia, G, Wang, J, Liao, P, Bartels, P, Zhang, H, Yu, D, Liang, MC, Poh, KK, Yu, CY, Jiang, F, Yong, TF, Wong, YP, Hu, Z, Huang, H, Zhang, G, Galupo, MJ, Bian, JS, Ponniah, S, Trasti, SL, See, K, Foo, R, Hoppe, UC, Herzig, S, Soong, TW (2017-05-23). Exclusion of alternative exon 33 of CaV1.2 calcium channels in heart is proarrhythmogenic. Proceedings of the National Academy of Sciences of the United States of America 114 (21) : E4288-E4295. ScholarBank@NUS Repository.
Abstract: Alternative splicing changes the CaV1.2 calcium channel electrophysiological property, but the in vivo significance of such altered channel function is lacking. Structure-function studies of heterologously expressed CaV1.2 channels could not recapitulate channel function in the native milieu of the cardiomyocyte. To address this gap in knowledge, we investigated the role of alternative exon 33 of the CaV1.2 calcium channel in heart function. Exclusion of exon 33 in CaV1.2 channels has been reported to shift the activation potential-10.4 mV to the hyperpolarized direction, and increased expression of CaV1.2δ33 channels was observed in rat myocardial infarcted hearts. However, how a change in CaV1.2 channel electrophysiological property, due to alternative splicing, might affect cardiac function in vivo is unknown. To address these questions, we generated mCacna1c exon 33-/-null mice. These mice contained CaV1.2δ33 channels with a gain-of-function that included conduction of larger currents that reflects a shift in voltage dependence and a modest increase in single-channel open probability. This altered channel property underscored the development of ventricular arrhythmia, which is reflected in significantly more deaths of exon 33-/- mice from β-adrenergic stimulation. In vivo telemetric recordings also confirmed increased frequencies in premature ventricular contractions, tachycardia, and lengthened QT interval. Taken together, the significant decrease or absence of exon 33-containing CaV1.2 channels is potentially proarrhythmic in the heart. Of clinical relevance, human ischemic and dilated cardiomyopathy hearts showed increased inclusion of exon 33. However, the possible role that inclusion of exon 33 in CaV1.2 channels may play in the pathogenesis of human heart failure remains unclear.
Source Title: Proceedings of the National Academy of Sciences of the United States of America
ISSN: 0027-8424
DOI: 10.1073/pnas.1617205114
Appears in Collections:Staff Publications

Show full item record
Files in This Item:
File Description SizeFormatAccess SettingsVersion 
pnas.1617205114.pdf1.39 MBAdobe PDF




checked on Jun 26, 2022

Page view(s)

checked on Jun 23, 2022


checked on Jun 23, 2022

Google ScholarTM



Items in DSpace are protected by copyright, with all rights reserved, unless otherwise indicated.