Li, Guang, Wang, Juejin, Liao, Ping, Bartels, Peter ORCID: 0000-0001-5852-1835, Zhang, Hengyu, Yu, Dejie, Liang, Mui Cheng ORCID: 0000-0003-1208-0733, Poh, Kian Keong, Yu, Chye Yun, Jiang, Fengli, Yong, Tan Fong, Wong, Yuk Peng, Hu, Zhenyu, Huang, Hua, Zhang, Guangqin, Galupo, Mary Joyce, Bian, Jin-Song, Ponniah, Sathivel, Trasti, Scott Lee, See, Kelvin, Foo, Roger ORCID: 0000-0002-8079-4618, Hoppe, Uta C., Herzig, Stefan and Soong, Tuck Wah (2017). Exclusion of alternative exon 33 of Ca(V)1.2 calcium channels in heart is proarrhythmogenic. Proc. Natl. Acad. Sci. U. S. A., 114 (21). S. E4288 - 8. WASHINGTON: NATL ACAD SCIENCES. ISSN 0027-8424

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Abstract

Alternative splicing changes the Ca(V)1.2 calcium channel electrophysiological property, but the in vivo significance of such altered channel function is lacking. Structure-function studies of heterologously expressed Ca(V)1.2 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 Ca(V)1.2 calcium channel in heart function. Exclusion of exon 33 in Ca(V)1.2 channels has been reported to shift the activation potential -10.4 mV to the hyperpolarized direction, and increased expression of Ca(V)1.2.33 channels was observed in rat myocardial infarcted hearts. However, how a change in Ca(V)1.2 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 Ca(V)1.2.33 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 beta-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 Ca(V)1.2 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 Ca(V)1.2 channels may play in the pathogenesis of human heart failure remains unclear.

Item Type: Journal Article
Creators:
CreatorsEmailORCIDORCID Put Code
Li, GuangUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Wang, JuejinUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Liao, PingUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Bartels, PeterUNSPECIFIEDorcid.org/0000-0001-5852-1835UNSPECIFIED
Zhang, HengyuUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Yu, DejieUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Liang, Mui ChengUNSPECIFIEDorcid.org/0000-0003-1208-0733UNSPECIFIED
Poh, Kian KeongUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Yu, Chye YunUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Jiang, FengliUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Yong, Tan FongUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Wong, Yuk PengUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Hu, ZhenyuUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Huang, HuaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Zhang, GuangqinUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Galupo, Mary JoyceUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Bian, Jin-SongUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Ponniah, SathivelUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Trasti, Scott LeeUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
See, KelvinUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Foo, RogerUNSPECIFIEDorcid.org/0000-0002-8079-4618UNSPECIFIED
Hoppe, Uta C.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Herzig, StefanUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Soong, Tuck WahUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
URN: urn:nbn:de:hbz:38-230782
DOI: 10.1073/pnas.1617205114
Journal or Publication Title: Proc. Natl. Acad. Sci. U. S. A.
Volume: 114
Number: 21
Page Range: S. E4288 - 8
Date: 2017
Publisher: NATL ACAD SCIENCES
Place of Publication: WASHINGTON
ISSN: 0027-8424
Language: English
Faculty: Unspecified
Divisions: Unspecified
Subjects: no entry
Uncontrolled Keywords:
KeywordsLanguage
CA2+ CHANNEL; EARLY AFTERDEPOLARIZATIONS; VENTRICULAR MYOCYTES; CARDIAC MYOCYTES; ALPHA(1) SUBUNIT; SPLICE VARIANTS; PURKINJE-FIBERS; TRANSGENIC MICE; FAILURE; CONTRACTIONMultiple languages
Multidisciplinary SciencesMultiple languages
Refereed: Yes
URI: http://kups.ub.uni-koeln.de/id/eprint/23078

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