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The Ca_V2.3 Ca²⁺ channel subunit contributes to R-type Ca²⁺ currents in murine hippocampal and neocortical neurones

Dmitry Sochivko *, Alexey Pereverzev †, Neil Smyth ‡, Cornelia Gissel †, Toni Schneider † and Heinz Beck *

Different subtypes of voltage-dependent Ca²⁺ currents in native neurones are essential in coupling action potential firing to Ca²⁺ influx. For most of these currents, the underlying Ca²⁺ channel subunits have been identified on the basis of pharmacological and biophysical similarities. In contrast, the molecular basis of R-type Ca²⁺ currents remains controversial. We have therefore examined the contribution of the Ca_V2.3 (_1E) subunits to R-type currents in different types of central neurones using wild-type mice and mice in which the Ca_V2.3 subunit gene was deleted. In hippocampal CA1 pyramidal cells and dentate granule neurones, as well as neocortical neurones of wild-type mice, Ca²⁺ current components resistant to the combined application of -conotoxin GVIA and MVIIC, -agatoxin IVa and nifedipine (I_Ca,R) were detected that were composed of a large R-type and a smaller T-type component. In Ca_V2.3-deficient mice, I_Ca,R was considerably reduced in CA1 neurones (79 %) and cortical neurones (87 %), with less reduction occurring in dentate granule neurones (47 %). Analysis of tail currents revealed that the reduction of I_Ca,R is due to a selective reduction of the rapidly deactivating R-type current component in CA1 and cortical neurones. In all cell types, I_Ca,R was highly sensitive to Ni²⁺ (100 µM: 71-86 % block). A selective antagonist of cloned Ca_V2.3 channels, the spider toxin SNX-482, partially inhibited I_Ca,R at concentrations up to 300 nM in dentate granule cells and cortical neurones (50 and 57 % block, EC₅₀ 30 and 47 nM, respectively). I_Ca,R in CA1 neurones was significantly less sensitive to SNX-482 (27 % block, 300 nM SNX-482). Taken together, our results show clearly that Ca_V2.3 subunits underlie a significant fraction of I_Ca,R in different types of central neurones. They also indicate that Ca_V2.3 subunits may give rise to Ca²⁺ currents with differing pharmacological properties in native neurones.

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