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RGK GTPase-dependent CaV2.1 Ca2+ channel inhibition is independent of CaV{beta}-subunit-induced current potentiation

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RGK (Rad-Gem-Rem) GTPases have been described as potent negative regulators of the Ca 2+ influx via high-threshold voltage-activated Ca 2+ channels. Recent work, mostly performed on Ca V 1.2 Ca 2+ channels, has highlighted the crucial role played by the channel auxiliary Ca V β subunits and identified several GTPase and β-subunit protein domains involved in this regulation. We now extend these conclusions by producing the first complete characterization of the effects of Gem, Rem, and Rem2 on the neuronal Ca V 2.1 Ca 2+ channels expressed with Ca V β 1 or Ca V β 2 subunits. Current inhibition is limited to a decrease in amplitude with no modification in the voltage dependence or kinetics of the current. We demonstrate that this inhibition can occur for Ca V β constructs with impaired capacity to induce current potentiation, but that it is lost for Ca V β constructs deleted for their β-interaction domain. The RGK C-terminal last 80 amino acids are sufficient to allow potent current inhibition and in vivo β-subunit/Gem interaction. Interestingly, although Gem and Gem carboxy-terminus induce a completely different pattern of β-subunit cellular localization, they both potently inhibit Ca V 2.1 channels. These data therefore set the status of neuronal Ca V 2.1 Ca 2+ channel inhibition by RGK GTPases, emphasizing the role of short amino acid sequences of both proteins in β-subunit binding and channel inhibition and revealing a new mechanism for channel inhibition.—Leyris, J.-P., Gondeau, C., Charnet, A., Delattre, C., Rousset, M., Cens, T., Charnet, P. RGK GTPase-dependent Ca V 2.1 Ca 2+ channel inhibition is independent of Ca V β-subunit-induced current potentiation.

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Article Details
Leyris, J.-P.; Gondeau, C.; Charnet, A.; Delattre, C.; Rousset, M.; Cens, T.; Charnet, P.
The FASEB Journal , Volume 23 (8): 2627
Fed of American Socs for Experimental BiologyAug 1, 2009
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