The alpha(2)delta subunit augments functional expression and modifies the pharmacology of Ca(V)1.3 L-type channels.

Academic Article

Abstract

  • The auxiliary Ca(V)alpha(2)delta-1 subunit is an important component of voltage-gated Ca(2+) (Ca(V)) channel complexes in many tissues and of great interest as a drug target. Nevertheless, its exact role in specific cell functions is still unknown. This is particularly important in the case of the neuronal L-type Ca(V) channels where these proteins play a key role in the secretion of neurotransmitters and hormones, gene expression, and the activation of other ion channels. Therefore, using a combined approach of patch-clamp recordings and molecular biology, we studied the role of the Ca(V)alpha(2)delta-1 subunit on the functional expression and the pharmacology of recombinant L-type Ca(V)1.3 channels in HEK-293 cells. Co-expression of Ca(V)alpha(2)delta-1 significantly increased macroscopic currents and conferred the Ca(V)1.3alpha(1)/Ca(V)beta(3) channels sensitivity to the antiepileptic/analgesic drugs gabapentin and AdGABA. In contrast, Ca(V)alpha(2)delta-1 subunits harboring point mutations in N-glycosylation consensus sequences or the proteolytic site as well as in conserved cysteines in the transmembrane delta domain of the protein, reduced functionality in terms of enhancement of Ca(V)1.3alpha(1)/Ca(V)beta(3) currents. In addition, co-expression of the delta domain drastically inhibited macroscopic currents through recombinant Ca(V)1.3 channels possibly by affecting channel synthesis. Together these results provide several lines of evidence that the Ca(V)alpha(2)delta-1 auxiliary subunit may interact with Ca(V)1.3 channels and regulate their functional expression.
  • Authors

  • Andrade, Arturo
  • Sandoval, Alejandro
  • González-Ramírez, Ricardo
  • Lipscombe, Diane
  • Campbell, Kevin P
  • Felix, Ricardo
  • Status

    Publication Date

  • October 2009
  • Published In

  • Cell Calcium  Journal
  • Keywords

  • Acetates
  • Amines
  • Animals
  • Calcium
  • Calcium Channel Blockers
  • Calcium Channels
  • Calcium Channels, L-Type
  • Cell Line
  • Cyclohexanecarboxylic Acids
  • Gabapentin
  • Humans
  • Patch-Clamp Techniques
  • Rabbits
  • Rats
  • Recombinant Fusion Proteins
  • gamma-Aminobutyric Acid
  • Digital Object Identifier (doi)

    Start Page

  • 282
  • End Page

  • 292
  • Volume

  • 46
  • Issue

  • 4