Targeted disruption of the voltage-dependent calcium channel α2/δ-1-subunit

作者：Geraldine A. Fuller-Bicer, Gyula Váradi, Sheryl E. Koch, Masakazu Ishii, Ilona Bódi, Nijiat Kadeer, James N. Muth, Gábor Mikala, Natalia N. Petrashevskaya, Michael A. Jordan, Sui‐Po Zhang, Na Qin, Christopher M. Flores, Idit Isaacsohn, Maria Varadi, Yasuo Mori, Walter Keith Jones, Arnold Schwartz · 发表于：American Journal of Physiology-Heart and Circulatory Physiology · 年份：2009 · DOI：10.1152/ajpheart.00122.2009 · 被引用次数：156 · 研究领域：Ion channel regulation and function、Cardiac electrophysiology and arrhythmias、Neuroscience and Neuropharmacology Research

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.