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Title: C-terminal alternative splicing of CaV1.3 channels distinctively modulates their dihydropyridine sensitivity
Authors: Huang, H.
Yu, D.
Soong, T.W. 
Issue Date: Oct-2013
Citation: Huang, H., Yu, D., Soong, T.W. (2013-10). C-terminal alternative splicing of CaV1.3 channels distinctively modulates their dihydropyridine sensitivity. Molecular Pharmacology 84 (4) : 643-653. ScholarBank@NUS Repository.
Abstract: The transcripts of L-type voltage-gated calcium channels (CaV) 1.3 undergo extensive alternative splicing. Alternative splicing, particularly in the C terminus, drastically modifies gating properties of the channel. However, little is known about whether alternative splicing could modulate the pharmacologic properties of CaV1.3 in a manner similar to the paralogous CaV1.2. Here we undertook the screening of different channel splice isoforms harboring splice variations in either the IS6 segment or the C terminus. Unexpectedly, while inclusion of exon 8a or 8, which code for IS6, did not alter dihydropyridine (DHP) sensitivity, distinct pharmacologic properties were observed for the various C-terminal splice isoforms. In the presence of external Ca2+, fast inactivating splice variants including CaV1.342a and CaV1.343s with intact calmodulin-IQ domain interaction showed consistently low DHP sensitivity. Interestingly, attenuation of calcium-dependent inactivation with overexpression of calmodulin34 did not enhance the sensitivity of CaV1.342a, suggesting that the low DHP sensitivity may not be a result of fast channel inactivation. Alternatively, disruption of calmodulin-IQ domain binding in the CaV1.3Δ41 and full-length CaV1.342 channels was associated with heightened DHP sensitivity. In distinct contrast to the well-known modulation of DHP blockade of CaV1.2 channels, this study has therefore uncovered a novel mechanism for modulation of the pharmacologic properties of Ca V1.3 channels through posttranscriptional modification of the C terminus. Copyright © 2013 by The American Society for Pharmacology and Experimental Therapeutics.
Source Title: Molecular Pharmacology
ISSN: 0026895X
DOI: 10.1124/mol.113.087155
Appears in Collections:Staff Publications

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