The Ca V 2.3 Ca 2+ channel subunit contributes to R‐Type Ca 2+ currents in murine hippocampal and neocortical neurones

Different subtypes of voltage‐dependent Ca 2+ currents in native neurones are essential in coupling action potential firing to Ca 2+ influx. For most of these currents, the underlying Ca 2+ channel subunits have been identified on the basis of pharmacological and biophysical similarities. In contrast, the molecular basis of R‐type Ca 2+ currents remains controversial. We have therefore examined the contribution of the Ca V 2.3 (α 1E ) subunits to R‐type currents in different types of central neurones using wild‐type mice and mice in which the Ca V 2.3 subunit gene was deleted. In hippocampal CA1 pyramidal cells and dentate granule neurones, as well as neocortical neurones of wild‐type mice, Ca 2+ current components resistant to the combined application of ω‐conotoxin GVIA and MVIIC, ω‐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 V 2.3‐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 Ni 2+ (100 μM: 71–86 % block). A selective antagonist of cloned Ca V 2.3 channels, the spider toxin SNX‐482, partially inhibited I Ca,R at concentrations up to 300 n m in dentate granule cells and cortical neurones (50 and 57 % block, EC 50 30 and 47 n m , respectively). I Ca,R in CA1 neurones was significantly less sensitive to SNX‐482 (27 % block, 300 n m SNX‐482). Taken together, our results show clearly that Ca V 2.3 subunits underlie a significant fraction of I Ca,R in different types of central neurones. They also indicate that Ca V 2.3 subunits may give rise to Ca 2+ currents with differing pharmacological properties in native neurones.