C-terminal alternative splicing of CaV1.3 channels distinctively modulates their dihydropyridine sensitivity

Mol Pharmacol. 2013 Oct;84(4):643-53. doi: 10.1124/mol.113.087155. Epub 2013 Aug 7.

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 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alternative Splicing / genetics*
  • Animals
  • Brain Chemistry / drug effects
  • Brain Chemistry / genetics
  • Calcium Channel Blockers / metabolism*
  • Calcium Channel Blockers / pharmacology
  • Calcium Channels / genetics*
  • Calcium Channels / metabolism*
  • Dihydropyridines / metabolism*
  • Dihydropyridines / pharmacology
  • HEK293 Cells
  • Humans
  • Protein Isoforms / genetics*
  • Protein Isoforms / metabolism
  • Rats

Substances

  • Calcium Channel Blockers
  • Calcium Channels
  • Dihydropyridines
  • Protein Isoforms
  • Cacna1d protein, rat
  • 1,4-dihydropyridine