Alternative Splicing as a Molecular Switch for Ca 2+ /Calmodulin-Dependent Facilitation of P/Q-Type Ca 2+ Channels

Alternative splicing of the P/Q-type channel (Ca V 2.1) promises customization of the computational repertoire of neurons. Here we report that concerted splicing of its main α 1A subunit, at both an EF-hand-like domain and the channel C terminus, controls the form of Ca 2+ -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 Ca 2+ influx through individual channels, (2) completely “OFF,” and (3) partially OFF but inducible by elevated global Ca 2+ 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.