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|Title:||Alternative splicing modulates diltiazem sensitivity of cardiac and vascular smooth muscle Ca v1.2 calcium channels||Authors:||Zhang, H.Y.
|Issue Date:||Aug-2010||Citation:||Zhang, H.Y., Liao, P., Wang, J.J., Yu, D.J., Soong, T.W. (2010-08). Alternative splicing modulates diltiazem sensitivity of cardiac and vascular smooth muscle Ca v1.2 calcium channels. British Journal of Pharmacology 160 (7) : 1631-1640. ScholarBank@NUS Repository.||Abstract:||Background and purpose: As a calcium channel blocker, diltiazem acts mainly on the voltage-gated calcium channels, Ca v1.2, 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 v1.2 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 v1.2 channels, predominant in cardiac and vascular smooth muscles. Experimental approach: Cardiac and smooth muscle isoforms of Ca v1.2 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 v1.2CM was less sensitive to diltiazem than two major smooth muscle splice variants, Ca v1.2SM and Ca v1.2b. Ca v1.2CM 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 v1.2CM channels. When we modified alternatively spliced exons of cardiac Ca v1.2CM 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 v1.2 channels modifies diltiazem sensitivity in the heart and blood vessels. Gating properties altered by diltiazem are different in the three channels. © 2010 The Authors. Journal compilation © 2010 The British Pharmacological Society.||Source Title:||British Journal of Pharmacology||URI:||http://scholarbank.nus.edu.sg/handle/10635/108253||ISSN:||00071188|
|Appears in Collections:||Staff Publications|
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