Targeted disruption of the voltage-dependent calcium channel alpha2/delta-1-subunit

Am J Physiol Heart Circ Physiol. 2009 Jul;297(1):H117-24. doi: 10.1152/ajpheart.00122.2009. Epub 2009 May 8.


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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Amines / metabolism
  • Animals
  • Binding Sites / drug effects
  • Binding Sites / genetics
  • Blotting, Western
  • Calcium Channels / drug effects
  • Calcium Channels / genetics
  • Calcium Channels / physiology*
  • Calcium Channels, L-Type / drug effects
  • Calcium Channels, L-Type / genetics
  • Calcium Channels, L-Type / physiology*
  • Cyclohexanecarboxylic Acids / metabolism
  • Electrophysiology
  • Exons / genetics
  • Gabapentin
  • Genotype
  • Heart / drug effects
  • Mice
  • Mice, Knockout
  • Muscle, Skeletal / cytology
  • Muscle, Skeletal / metabolism
  • Myocardial Contraction / drug effects
  • Myocardial Contraction / genetics
  • Myocytes, Cardiac / drug effects
  • Patch-Clamp Techniques
  • Reverse Transcriptase Polymerase Chain Reaction
  • gamma-Aminobutyric Acid / metabolism


  • Amines
  • CACNA2D1 protein, mouse
  • Calcium Channels
  • Calcium Channels, L-Type
  • Cyclohexanecarboxylic Acids
  • gamma-Aminobutyric Acid
  • Gabapentin