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Alternative splicing modulates diltiazem sensitivity of cardiac and vascular smooth muscle Ca v 1.2 calcium channels
Author(s) -
Zhang Heng Yu,
Liao Ping,
Wang Jue Jin,
Yu De Jie,
Soong Tuck Wah
Publication year - 2010
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1111/j.1476-5381.2010.00798.x
Subject(s) - diltiazem , vascular smooth muscle , alternative splicing , cardiac action potential , voltage dependent calcium channel , medicine , splice , endocrinology , calcium , chemistry , electrophysiology , biology , gene isoform , repolarization , biochemistry , smooth muscle , gene
Background and purpose: As a calcium channel blocker, diltiazem acts mainly on the voltage‐gated calcium channels, Ca v 1.2, for its beneficial effects in cardiovascular diseases such as hypertension, angina and/or supraventricular arrhythmias. However, the effects of diltiazem on different isoforms of Ca v 1.2 channels expressed in heart and vascular smooth muscles remain to be investigated. Here, we characterized the effects of diltiazem on the splice variants of Ca v 1.2 channels, predominant in cardiac and vascular smooth muscles. Experimental approach: Cardiac and smooth muscle isoforms of Ca v 1.2 channels were expressed in human embryonic kidney cells and their electrophysiological properties were characterized using whole‐cell patch‐clamp techniques. Key results: Under closed‐channel and use‐dependent block (0.03 Hz), cardiac splice variant Ca v 1.2CM was less sensitive to diltiazem than two major smooth muscle splice variants, Ca v 1.2SM and Ca v 1.2b. Ca v 1.2CM has a more positive half‐inactivation potential than the smooth muscle channels, and diltiazem shifted it less to negative potential. Additionally, the current decay was slower in Ca v 1.2CM channels. When we modified alternatively spliced exons of cardiac Ca v 1.2CM channels into smooth muscle exons, we found that all three loci contribute to the different diltiazem sensitivity between cardiac and smooth muscle splice isoforms. Conclusions and implications: Alternative splicing of Ca v 1.2 channels modifies diltiazem sensitivity in the heart and blood vessels. Gating properties altered by diltiazem are different in the three channels.