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The Journal of Neuroscience, July 14, 2004, 24(28):6334-6342; doi:10.1523/JNEUROSCI.1712-04.2004

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

Dipayan Chaudhuri,¹ Siao-Yun Chang,³ Carla D. DeMaria,^2,4 Rebecca S. Alvania,¹ Tuck Wah Soong,^3,5 and David T. Yue^1,2

Departments of ¹Neuroscience and ²Biomedical Engineering, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, ³National Neuroscience Institute, Singapore 308433, ⁴Office of Technology Licensing, Georgetown University, Washington, DC 20057, and ⁵Department of Physiology, National University of Singapore, Singapore 117597

Alternative splicing of the P/Q-type channel (Ca_V2.1) promises customization of the computational repertoire of neurons. Here we report that concerted splicing of its main _1A subunit, 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.

Key words: Ca_V2.1; EF hand; short-term synaptic plasticity; Ca²⁺-dependent inactivation; developmental alternative splicing; exon 37

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Received May 4, 2004; revised May 26, 2004; accepted May 26, 2004.

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