C-terminal alternative splicing of CaV1.3 channels distinctively modulates their dihydropyridine sensitivity.
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 Ca(2+), 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 CaV1.3 channels through posttranscriptional modification of the C terminus.
Department of Physiology, Yong Loo Lin School of Medicine (H.H., D.Y., T.W.S.), NUS Graduate School for Integrative Sciences and Engineering (T.W.S.), and Neurobiology/Ageing Programme, National University of Singapore, and National Neuroscience Institute, Singapore (T.W.S.).
Hua
H
Huang
Dejie
D
Yu
Tuck Wah
TW
Soong
D017398:Alternative Splicing / Q000235:genetics*; D000818:Animals; D001923:Brain Chemistry / Q000187:drug effects / Q000235:genetics; D002121:Calcium Channel Blockers / Q000378:metabolism* / Q000494:pharmacology; D015220:Calcium Channels / Q000235:genetics* / Q000378:metabolism*; D004095:Dihydropyridines / Q000378:metabolism* / Q000494:pharmacology; D057809:HEK293 Cells; D006801:Humans; D020033:Protein Isoforms / Q000235:genetics* / Q000378:metabolism; D051381:Rats
D002121:Calcium Channel Blockers; D015220:Calcium Channels; D004095:Dihydropyridines; D020033:Protein Isoforms; C093712:Cacna1d protein, rat; C038806:1,4-dihydropyridine