title: The Ca(V)2.3 Ca(2+) channel subunit contributes to R-type Ca(2+) currents in murine hippocampal and neocortical neurones.
abstract: 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 (alpha(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 omega-conotoxin GVIA and MVIIC, omega-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 microM: 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 nM in dentate granule cells and cortical neurones (50 and 57 % block, EC(50) 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(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.
authors.affiliation: Department of Epileptology, University of Bonn Medical Center, Sigmund-Freud Str. 25, 53105 Bonn, Germany.
authors.forename: Dmitry
authors.initials: D
authors.lastname: Sochivko
authors.forename: Alexey
authors.initials: A
authors.lastname: Pereverzev
authors.forename: Neil
authors.initials: N
authors.lastname: Smyth
authors.forename: Cornelia
authors.initials: C
authors.lastname: Gissel
authors.forename: Toni
authors.initials: T
authors.lastname: Schneider
authors.forename: Heinz
authors.initials: H
authors.lastname: Beck
mesh_terms: D000818:Animals; D002121:Calcium Channel Blockers / Q000494:pharmacology; D020908:Calcium Channels, R-Type / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D020747:Calcium Channels, T-Type / Q000187:drug effects / Q000502:physiology*; D018891:Dentate Gyrus / Q000378:metabolism; D004351:Drug Resistance; D004553:Electric Conductivity; D004594:Electrophysiology; D006624:Hippocampus / Q000378:metabolism*; D026901:Membrane Transport Proteins; D051379:Mice; D018345:Mice, Knockout / Q000235:genetics; D019579:Neocortex / Q000378:metabolism*; D009474:Neurons / Q000378:metabolism*; D017966:Pyramidal Cells / Q000378:metabolism; D012016:Reference Values
chemical_list: C469757:CACNA1I protein, human; D002121:Calcium Channel Blockers; D020908:Calcium Channels, R-Type; D020747:Calcium Channels, T-Type; D026901:Membrane Transport Proteins