Abstract
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 alpha1A 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.
Publication types
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Alternative Splicing*
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Amino Acid Sequence
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Animals
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Calcium / metabolism
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Calcium Channels / chemistry
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Calcium Channels / genetics*
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Calcium Channels, L-Type / chemistry
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Calcium Channels, L-Type / genetics
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Calcium Channels, N-Type
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Calcium Channels, P-Type
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Calcium Channels, Q-Type
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Calmodulin / chemistry
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Calmodulin / pharmacology
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Calmodulin / physiology*
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Cell Line
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Exons / genetics
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Ion Transport / drug effects
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Kidney
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Mice
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Models, Molecular
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Molecular Sequence Data
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Neurons / metabolism
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Polymerase Chain Reaction
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Protein Conformation
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Protein Interaction Mapping
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Protein Structure, Tertiary
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Recombinant Fusion Proteins / chemistry
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Transfection
Substances
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Cacnb2 protein, mouse
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Calcium Channels
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Calcium Channels, L-Type
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Calcium Channels, N-Type
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Calcium Channels, P-Type
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Calcium Channels, Q-Type
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Calmodulin
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Recombinant Fusion Proteins
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voltage-dependent calcium channel (P-Q type)
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Cacna1d protein, rat
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Calcium