Alternative Splicing as a Molecular Switch for Ca2+/Calmodulin-Dependent Facilitation of P/Q-Type Ca2+Channels

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Abstract
Alternative splicing of the P/Q-type channel (CaV2.1) promises customization of the computational repertoire of neurons. Here we report that concerted splicing of its main α1Asubunit, at both an EF-hand-like domain and the channel C terminus, controls the form of Ca2+-dependent facilitation (CDF), an activity-dependent enhancement of channel opening that is triggered by calmodulin. In recombinant channels, such alternative splicing switches CDF among three modes: (1) completely “ON” and driven by local Ca2+influx through individual channels, (2) completely “OFF,” and (3) partially OFF but inducible by elevated global Ca2+influx. Conversion from modes 1 to 3 represents an unprecedented dimension of control. The physiological function of these variants is likely important, because we find that the distribution of EF-hand splice variants is strikingly heterogeneous in the human brain, varying both across regions and during development.