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Am J Physiol Heart Circ Physiol 297: H117-H124, 2009. First published May 8, 2009; doi:10.1152/ajpheart.00122.2009
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Targeted disruption of the voltage-dependent calcium channel {alpha}2/{delta}-1-subunit

Geraldine A. Fuller-Bicer,1,* Gyula Varadi,1,* Sheryl E. Koch,1,* Masakazu Ishii,1,* Ilona Bodi,1 Nijiat Kadeer,2 James N. Muth,1 Gabor Mikala,1 Natalia N. Petrashevskaya,1 Michael A. Jordan,3 Sui-Po Zhang,4 Ning Qin,4 Christopher M. Flores,4 Idit Isaacsohn,1 Maria Varadi,1 Yasuo Mori,1 W. Keith Jones,2 and Arnold Schwartz1

1Institute of Molecular Pharmacology and Biophysics, Department of Surgery, and 2Department of Pharmacology and Cell Biophysics, University of Cincinnati, College of Medicine, Cincinnati, Ohio; 3DNA Analysis, LLC, Cincinnati, Ohio; and 4Division of Analgesics, Drug Discovery, Johnson & Johnson Pharmaceutical Research and Development, Spring House, Pennsylvania

Submitted 4 February 2009 ; accepted in final form 6 May 2009

Cardiac L-type voltage-dependent Ca2+ channels are heteromultimeric polypeptide complexes of {alpha}1-, {alpha}2/{delta}-, and β-subunits. The {alpha}2/{delta}-1-subunit possesses a stereoselective, high-affinity binding site for gabapentin, widely used to treat epilepsy and postherpetic neuralgic pain as well as sleep disorders. Mutations in {alpha}2/{delta}-subunits of voltage-dependent Ca2+ channels have been associated with different diseases, including epilepsy. Multiple heterologous coexpression systems have been used to study the effects of the deletion of the {alpha}2/{delta}-1-subunit, but attempts at a conventional knockout animal model have been ineffective. We report the development of a viable conventional knockout mouse using a construct targeting exon 2 of {alpha}2/{delta}-1. While the deletion of the subunit is not lethal, these animals lack high-affinity gabapentin binding sites and demonstrate a significantly decreased basal myocardial contractility and relaxation and a decreased L-type Ca2+ current peak current amplitude. This is a novel model for studying the function of the {alpha}2/{delta}-1-subunit and will be of importance in the development of new pharmacological therapies.

cardiac calcium channel; murine knockout model; gabapentin binding; myocardial contractility


Address for reprint requests and other correspondence: A. Schwartz, Inst. of Molecular Pharmacology and Biophysics, Dept. of Surgery, Univ. of Cincinnati, College of Medicine, 231 Albert Sabin Way, Cincinnati, OH 45267-0828 (e-mail: schwara{at}ucemail.uc.edu)






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