The Journal of General Physiology
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Published online Sep 26 2005. doi:10.1085/jgp.200509354
The Rockefeller University Press, 0022-1295 $8.00
JGP, Volume 126, Number 4, 365-377
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ARTICLE

 A CaVß SH3/Guanylate Kinase Domain Interaction Regulates Multiple Properties of Voltage-gated Ca2+ Channels

Shoji X. Takahashi, Jayalakshmi Miriyala, Lai Hock Tay, David T. Yue, and Henry M. Colecraft

Calcium Signals Laboratory, Department of Biomedical Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205

Correspondence to Henry M. Colecraft: hcolecr1{at}jhmi.edu

Auxiliary Ca2+ channel ß subunits (CaVß) regulate cellular Ca2+ signaling by trafficking pore-forming {alpha}1 subunits to the membrane and normalizing channel gating. These effects are mediated through a characteristic src homology 3/guanylate kinase (SH3–GK) structural module, a design feature shared in common with the membrane-associated guanylate kinase (MAGUK) family of scaffold proteins. However, the mechanisms by which the CaVß SH3–GK module regulates multiple Ca2+ channel functions are not well understood. Here, using a split-domain approach, we investigated the role of the interrelationship between CaVß SH3 and GK domains in defining channel properties. The studies build upon a previously identified split-domain pair that displays a trans SH3–GK interaction, and fully reconstitutes CaVß effects on channel trafficking, activation gating, and increased open probability (Po). Here, by varying the precise locations used to separate SH3 and GK domains and monitoring subsequent SH3–GK interactions by fluorescence resonance energy transfer (FRET), we identified a particular split-domain pair that displayed a subtly altered configuration of the trans SH3–GK interaction. Remarkably, this pair discriminated between CaVß trafficking and gating properties: {alpha}1C targeting to the membrane was fully reconstituted, whereas shifts in activation gating and increased Po functions were selectively lost. A more extreme case, in which the trans SH3–GK interaction was selectively ablated, yielded a split-domain pair that could reconstitute neither the trafficking nor gating-modulation functions, even though both moieties could independently engage their respective binding sites on the {alpha}1C (CaV1.2) subunit. The results reveal that CaVß SH3 and GK domains function codependently to tune Ca2+ channel trafficking and gating properties, and suggest new paradigms for physiological and therapeutic regulation of Ca2+ channel activity.

Abbreviations used in this paper: AID, {alpha}1 interaction domain; CaVß, Ca2+ channel ß subunit; CFP, cyan fluorescent protein; FR, FRET ratio; FRET, fluorescence resonance energy transfer; GK, guanylate kinase; MAGUK, membrane-associated guanylate kinase; Po, open probability; SH3, src homology 3; YFP, yellow fluorescent protein.


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