C-Terminal Alternative Splicing of CaV1.3 Channels Distinctively Modulates Their Dihydropyridine Sensitivity

The transcripts of L-type voltage-gated calcium channels (Ca-V) 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 Ca(V)1.3 in a manner similar to the paralogous Ca(V)1.2. 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 Ca(V)1.3(42a) and Ca(V)1.3(43s) with intact calmodulin-IQ domain interaction showed consistently low DHP sensitivity. Interestingly, attenuation of calcium-dependent inactivation with overexpression of calmodulin(34) did not enhance the sensitivity of Ca(V)1.3(42a), suggesting that the low DHP sensitivity may not be a result of fast channel inactivation. Alternatively, disruption of calmodulin-IQ domain binding in the Ca(V)1.3(Delta 41) and full-length Ca(V)1.3(42) channels was associated with heightened DHP sensitivity. In distinct contrast to the well-known modulation of DHP blockade of Ca(V)1.2 channels, this study has therefore uncovered a novel mechanism for modulation of the pharmacologic properties of Ca(V)1.3 channels through posttranscriptional modification of the C terminus.