The CaV2.3 Ca2+ channel subunit contributes to R-Type Ca2+ currents in murine hippocampal and neocortical neurones

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Abstract

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 CaV2.3 (α1E) subunits to R-type currents in different types of central neurones using wild-type mice and mice in which the CaV2.3 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 ω-conotoxin GVIA and MVIIC, ω-agatoxin IVa and nifedipine (ICa,R) were detected that were composed of a large R-type and a smaller T-type component. In CaV2.3-deficient mice, ICa,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 ICa,R is due to a selective reduction of the rapidly deactivating R-type current component in CA1 and cortical neurones. In all cell types, ICa,R was highly sensitive to Ni2+ (100 μM: 71–86 % block). A selective antagonist of cloned CaV2.3 channels, the spider toxin SNX-482, partially inhibited ICa,R at concentrations up to 300 nm in dentate granule cells and cortical neurones (50 and 57 % block, EC50 30 and 47 nm, respectively). ICa,R in CA1 neurones was significantly less sensitive to SNX-482 (27 % block, 300 nm SNX-482). Taken together, our results show clearly that CaV2.3 subunits underlie a significant fraction of ICa,R in different types of central neurones. They also indicate that CaV2.3 subunits may give rise to Ca2+ currents with differing pharmacological properties in native neurones.

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