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Originally published In Press as doi:10.1074/jbc.M203425200 on August 2, 2002

J. Biol. Chem., Vol. 277, Issue 43, 40342-40351, October 25, 2002
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Pain Perception in Mice Lacking the beta 3 Subunit of Voltage-activated Calcium Channels*

Manabu MurakamiDagger §, Bernd Fleischmann, Carmen De Felipe||, Marc FreichelDagger , Claudia TrostDagger , Andreas Ludwig**, Ulrich WissenbachDagger , Herbert SchweglerDagger Dagger , Franz Hofmann**, Jürgen Hescheler, Veit FlockerziDagger , and Adolfo CavaliéDagger §§

From the Dagger  Pharmakologie und Toxikologie, Universität des Saarlandes, D-66421 Homburg, Germany, § Molecular Pharmacology, Tohoku University School of Medicine, Sendai 980, Japan,  Institut für Neurophysiologie, Universität zu Köln, D-50931 Köln, Germany, || Instituto de Neurosciencias, Universidad Miguel Hernandez, 03550 San Juan de Alicante, Spain, ** Institut für Pharmakologie und Toxikologie, TU München, D-80802 München, Germany, Dagger Dagger  Institut für Anatomie, Universität Magdeburg, D-39120 Magdeburg, Germany

The importance of voltage-activated calcium channels in pain processing has been suggested by the spinal antinociceptive action of blockers of N- and P/Q-type calcium channels as well as by gene targeting of the alpha 1B subunit (N-type). The accessory beta 3 subunits of calcium channels are preferentially associated with the alpha 1B subunit in neurones. Here we show that deletion of the beta 3 subunit by gene targeting affects strongly the pain processing of mutant mice. We pinpoint this defect in the pain-related behavior and ascending pain pathways of the spinal cord in vivo and at the level of calcium channel currents and proteins in single dorsal root ganglion neurones in vitro. The pain induced by chemical inflammation is preferentially damped by deletion of beta 3 subunits, whereas responses to acute thermal and mechanical harmful stimuli are reduced moderately or not at all, respectively. The defect results in a weak wind-up of spinal cord activity during intense afferent nerve stimulation. The molecular mechanism responsible for the phenotype was traced to low expression of N-type calcium channels (alpha 1B) and functional alterations of calcium channel currents in neurones projecting to the spinal cord.


* This study was supported by grants from the Deutsche Forschungsgemeinschaft and Fonds der Chemie (to V. F.).The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

§§ To whom correspondence should be addressed. Tel.: 49-6841-1626151; Fax: 49-6841-1626402; E-mail: adolfo.cavalie@uniklinik-saarland.de.


Copyright © 2002 by The American Society for Biochemistry and Molecular Biology, Inc.
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