Targeted disruption of the voltage-dependent calcium channel alpha2/delta-1-subunit.
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.
Institute of Molecular Pharmacology and Biophysics, Department of Surgery, University of Cincinnati, College of Medicine, Cincinnati, OH 45267-0828, USA.
Geraldine A
GA
Fuller-Bicer
Gyula
G
Varadi
Sheryl E
SE
Koch
Masakazu
M
Ishii
Ilona
I
Bodi
Nijiat
N
Kadeer
James N
JN
Muth
Gabor
G
Mikala
Natalia N
NN
Petrashevskaya
Michael A
MA
Jordan
Sui-Po
SP
Zhang
Ning
N
Qin
Christopher M
CM
Flores
Idit
I
Isaacsohn
Maria
M
Varadi
Yasuo
Y
Mori
W Keith
WK
Jones
Arnold
A
Schwartz
D000588:Amines / Q000378:metabolism; D000818:Animals; D001665:Binding Sites / Q000187:drug effects / Q000235:genetics; D015153:Blotting, Western; D015220:Calcium Channels / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D020746:Calcium Channels, L-Type / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D003509:Cyclohexanecarboxylic Acids / Q000378:metabolism; D004594:Electrophysiology; D005091:Exons / Q000235:genetics; D000077206:Gabapentin; D005838:Genotype; D006321:Heart / Q000187:drug effects; D051379:Mice; D018345:Mice, Knockout; D018482:Muscle, Skeletal / Q000166:cytology / Q000378:metabolism; D009200:Myocardial Contraction / Q000187:drug effects / Q000235:genetics; D032383:Myocytes, Cardiac / Q000187:drug effects; D018408:Patch-Clamp Techniques; D020133:Reverse Transcriptase Polymerase Chain Reaction; D005680:gamma-Aminobutyric Acid / Q000378:metabolism
D000588:Amines; C512066:CACNA2D1 protein, mouse; D015220:Calcium Channels; D020746:Calcium Channels, L-Type; D003509:Cyclohexanecarboxylic Acids; D005680:gamma-Aminobutyric Acid; D000077206:Gabapentin