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.
Fuller-Bicer
Geraldine A
GA
Institute of Molecular Pharmacology and Biophysics, Department of Surgery, University of Cincinnati, College of Medicine, Cincinnati, OH 45267-0828, USA.
Varadi
Gyula
G
Koch
Sheryl E
SE
Ishii
Masakazu
M
Bodi
Ilona
I
Kadeer
Nijiat
N
Muth
James N
JN
Mikala
Gabor
G
Petrashevskaya
Natalia N
NN
Jordan
Michael A
MA
Zhang
Sui-Po
SP
Qin
Ning
N
Flores
Christopher M
CM
Isaacsohn
Idit
I
Varadi
Maria
M
Mori
Yasuo
Y
Jones
W Keith
WK
Schwartz
Arnold
A
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