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J Physiol Volume 586, Number 22, 5349-5366, November 15, 2008 DOI: 10.1113/jphysiol.2008.159111
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MOLECULAR AND GENOMIC

A critical GxxxA motif in the {gamma}6 calcium channel subunit mediates its inhibitory effect on Cav3.1 calcium current

 Zuojun Lin1, Katja Witschas2, Thomas Garcia1, Ren-Shiang Chen1, Jared P. Hansen1, Zachary M. Sellers1,3, Elza Kuzmenkina2, Stefan Herzig2 and Philip M. Best1,3

1 Department of Molecular and Integrative Physiology, University of Illinois at Urbana-Champaign, Urbana, IL 61801, USA
2 Department of Pharmacology and Center for Molecular Medicine, University of Cologne, 50931 Cologne, Germany
3 College of Medicine, University of Illinois at Urbana-Champaign, Urbana, IL 61801, USA

The eight members of the calcium channel {gamma} subunit family are integral membrane proteins that regulate the expression and behaviour of voltage and ligand gated ion channels. While a subgroup consisting of {gamma}2, {gamma}3, {gamma}4 and {gamma}8 (the TARPs) modulate AMPA receptor localization and function, the {gamma}1 and {gamma}6 subunits conform to the original description of these proteins as regulators of voltage gated calcium channels. We have previously shown that the {gamma}6 subunit is highly expressed in atrial myocytes and that it is capable of acting as a negative modulator of low voltage activated calcium current. In this study we extend our understanding of {gamma}6 subunit modulation of low voltage activated calcium current. Using engineered chimeric constructs, we demonstrate that the first transmembrane domain (TM1) of {gamma}6 is necessary for its inhibitory effect on Cav3.1 current. Mutational analysis is then used to identify a unique GxxxA motif within TM1 that is required for the function of the subunit strongly suggesting the involvement of helix–helix interactions in its effects. Results from co-immunoprecipitation experiments confirm a physical association of {gamma}6 with the Cav3.1 channel in both HEK cells and atrial myocytes. Single channel analysis reveals that binding of {gamma}6 reduces channel availability for activation. Taken together, the results of this study provide both a molecular and a mechanistic framework for understanding the unique ability of the {gamma}6 calcium channel subunit to modulate low voltage activated (Cav3.1) calcium current density.

(Received 3 July 2008; accepted after revision 18 September 2008; first published online 25 September 2008)
Corresponding author P. M. Best: 524 Burrill Hall, MC-114, 407 South Goodwin Avenue, Urbana, IL 61801, USA. Email: pbest{at}illinois.edu


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