Submitted on February 4, 2009
Revised on March 20, 2009
Accepted on May 6, 2009
Targeted Disruption of the Voltage-Dependent Ca2+ Channel 
2/
-1 Subunit
Geraldine A Fuller-Bicer1, Gyula Varadi2, Sheryl E Koch1, Masakazu Ishii1, Ilona Bodi1, Nijiat Kadeer1, James N. Muth1, Gabor Mikala1, Natalia N Petrashevskaya1, Michael A Jordan1, Sui-Po Zhang3, Ning Qin3, Christopher M. Flores3, Idit Isaacsohn1, Maria Varadi1, Yasuo Mori4, W. Keith Jones1, and Arnold Schwartz5*
1 University of Cincinnati
2 Radiation Monitoring Devices Inc
3 Johnson & Johnson Pharmaceutical Research and Development
4 Kyoto University
5 University of Cincinnati College of Medicine
* To whom correspondence should be addressed. E-mail: schwara{at}email.uc.edu.
Cardiac L-type voltage dependent calcium channels (L-VDCCs) are heteromultimeric polypeptide complexes of 
1, 2/
, and 
subunits. The 2/-1 subunit possesses a stereo-selective, high-affinity binding site for gabapentin (GBP) widely used to treat epilepsy and post-herpetic neuralgic pain as well as sleep disorders. Mutations in 2/ subunits of VDCCs have been associated with different diseases, including epilepsy. Multiple heterologous co-expression systems have been used to study the effects of deletion of the 2/-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 2/-1. While the deletion of the subunit is not lethal, these animals lack high-affinity gabapentin binding sites, demonstrate significantly decreased basal myocardial contractility and relaxation, and decreased ICa peak current amplitude. This is a novel model for studying the function of the 2/-1 subunit and will be of importance in the development of new pharmacological therapies.
