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

Fuller-Bicer GA, Varadi G, Koch SE, Ishii M, Bodi I, Kadeer N, Muth JN, Mikala G, Petrashevskaya NN, Jordan MA, Zhang S, Qin N, Flores CM, Isaacsohn I, Varadi M, Mori Y, Jones WK, Schwartz A. Targeted disruption of the voltage-dependent calcium channel alpha(2)/delta 1-subunit. Am J Physiol Heart Circ Physiol 297: H117-H124, 2009. First published May 8, 2009; doi:10.1152/ajpheart.00122.2009.-Cardiac L-type voltage-dependent Ca2+ 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 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.