Two sets of amino acids of the domain I of Cav2.3 Ca2+ channels contribute to their high sensitivity to extracellular protons
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Extracellular acidification decreases Ca2+ current amplitude and produces a depolarizing shift in the activation potential (Va) of voltage-gated Ca2+ channels (VGCC). These effects are common to all VGCC, but differences exist between Ca2+ channel types and the underlying molecular mechanisms remain largely unknown. We report here that the changes in current amplitude induced by extracellular acidification or alkalinisation are more important for Cav2.3 R type than for Cav2.1 P/Q-type Ca2+ channels. This difference results from a higher shift of Va combined with a modification of channel conductance. Although involved in the sensitivity of channel conductance to extracellular protons, neither the EEEE locus nor the divalent cation selectivity locus could explain the specificity of the pH effects. We show that this specificity involves two separate sets of amino acids within domain I of the Cavα subunit. Residues of the voltage sensor domain and residues in the pore domain mediate the effects of extracellular protons on Va and on channel conductance, respectively. These new insights are important for elucidating the molecular mechanisms that control VGCC gating and conductance and for understanding the role of extracellular protons in other channels or membrane-tethered enzymes with similar pore and/or voltage sensor domains.
KeywordsVoltage-gated Ca2+ channels Extracellular pH Conductance Gating
Voltage-gated Ca2+ channels
High voltage activated
Low voltage activated
Divalent cations selectivity
Voltage sensor domain
Maximal whole cell conductance
This work was supported by the “Centre Nationale de la Recherche Scientifique”, the “Institut Nationale de la Santé Et de la Recherche Médicale”, the “Fondation Simone & Cino Del Duca”, the “Fondation pour la Recherche sur le Cerveau”. We thank T. Snutch and E. Perez-Reyes for kindly providing calcium channels cDNAs, J-M. Donnay and J-C Mazur for oocyte preparations.
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