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Targeted disruption of the voltage-dependent calcium channel alpha2/delta-1-subunit.

Authors
  • Fuller-Bicer, Geraldine A
  • Varadi, Gyula
  • Koch, Sheryl E
  • Ishii, Masakazu
  • Bodi, Ilona
  • Kadeer, Nijiat
  • Muth, James N
  • Mikala, Gabor
  • Petrashevskaya, Natalia N
  • Jordan, Michael A
  • Zhang, Sui-Po
  • Qin, Ning
  • Flores, Christopher M
  • Isaacsohn, Idit
  • Varadi, Maria
  • Mori, Yasuo
  • Jones, W Keith
  • Schwartz, Arnold
Type
Published Article
Journal
American journal of physiology. Heart and circulatory physiology
Publication Date
Jul 01, 2009
Volume
297
Issue
1
Identifiers
DOI: 10.1152/ajpheart.00122.2009
PMID: 19429829
Source
Medline
License
Unknown

Abstract

Cardiac L-type voltage-dependent Ca(2+) channels are heteromultimeric polypeptide complexes of alpha(1)-, alpha(2)/delta-, and beta-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 Ca(2+) 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 Ca(2+) 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.

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