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First published online on June 7, 2002.
Copyright © 2002 by The Physiological Society
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Received March 17, 2002
Accepted after revision May 15, 2002

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

Dmitry Sochivko1, Alexey Pereverzev2, Neil Smyth3, Cornelia Gissel2, Toni Schneider{dagger}2, and Heinz Beck4*

1 Department of Epileptology, University of Bonn Medical Center, Sigmund-Freud Str. 25, 53105 Bonn, Germany
2 Department of Neurophysiology, University of Cologne, Robert-Koch-Str. 39, 50931 Cologne, Germany
3 Department of Biochemistry, University of Cologne, Joseph Stelzmann-Str. 52, 50931 Cologne, Germany
4 Department of Epileptology, University of Bonn Medical Center, Sigmund-Freud Str. 25, D-53105 Bonn, Germany

* To whom correspondence should be addressed. E-mail: heinz.beck{at}ukb.uni-bonn.de.

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 ({alpha}1E) 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 {omega}-conotoxin GVIA and MVIIC, {omega}-agatoxin IVa and nifedipine (ICa,R) were detected (ICa,R) 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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