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RGK GTPase-dependent Ca_V2.1 Ca²⁺ channel inhibition is independent of Ca_Vβ-subunit-induced current potentiation

CRBM, CNRS, UMR 5237, Université de Montpellier 1 & 2, Montpellier, France

¹ Correspondence: CRBM, CNRS UMR 5237, 1919 Rte. de Mende, 34293 Montpellier cedex, France. E-mail: pierre.charnet{at}crbm.cnrs.fr

RGK (Rad-Gem-Rem) GTPases have been described as potent negative regulators of the Ca²⁺ influx via high-threshold voltage-activated Ca²⁺ channels. Recent work, mostly performed on Ca_V1.2 Ca²⁺ channels, has highlighted the crucial role played by the channel auxiliary Ca_Vβ 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_V2.1 Ca²⁺ channels expressed with Ca_Vβ₁ or Ca_Vβ₂ 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_Vβ constructs with impaired capacity to induce current potentiation, but that it is lost for Ca_Vβ 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_V2.1 channels. These data therefore set the status of neuronal Ca_V2.1 Ca²⁺ 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_V2.1 Ca²⁺ channel inhibition is independent of Ca_Vβ-subunit-induced current potentiation.

Key Words: Gem • Rem • Rem2 • Xenopus oocytes • GK domain