Differential effect of gabapentin on neuronal and muscle calcium currents.
Calcium channels modulate cell function by controlling Ca(2+) influx. A main component of these proteins is the alpha 2/delta subunit. Nevertheless, how this subunit regulates channel activity in situ is unclear. Gabapentin (GBP), an analgesic and anti-epileptic agent with an unknown mechanism of action, specifically binds to the alpha 2/delta subunit. Using the patch clamp technique, we tested the effects of GBP on Ca(2+) currents from dorsal root ganglion (DRG) cells, the mediators of pain perception, to determine how GBP binding modifies channel activity. In DRGs, GBP significantly reduced whole cell Ca(2+) current amplitude at positive membrane potentials when a pulse preceded the test pulses or when cells were stimulated with a train of pulses. In control cells, neither prepulse depolarization nor pulse trains reduced Ca(2+) currents at positive potentials. GBP did not reduce the low-voltage activated Ca(2+) current under any experimental condition. Similar to DRG cells, GBP attenuated Ca(2+) current in skeletal myotubes at positive membrane potentials in the presence of a depolarizing prepulse. However, GBP did not significantly alter Ca(2+) currents in cardiac myocytes. Reverse transcription-polymerase chain reaction was used to confirm expression of the alpha 2/delta subunit in these cells. Each cell type expressed multiple isoforms of alpha 2/delta. Muscle cells showed a more variable expression of alpha 2/delta subunits than did DRG cells. Our results suggest a possible participation of the alpha 2/delta subunit in the action of GBP. Our data also indicate that GBP inhibits Ca(2+) channels in a use- and voltage-dependent manner at a therapeutically relevant concentration.
Alden
K J
KJ
Department of Physiology & Biophysics, University of Illinois at Chicago College of Medicine, Chicago, Illinois 60607, USA.
García
J
J
D000085:Acetates / Q000494:pharmacology*; D000588:Amines; D000818:Animals; D015220:Calcium Channels / Q000187:drug effects / Q000378:metabolism*; D002478:Cells, Cultured; D003509:Cyclohexanecarboxylic Acids; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology*; D000077206:Gabapentin; D005727:Ganglia, Spinal / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D006321:Heart / Q000187:drug effects; D008564:Membrane Potentials / Q000187:drug effects; D051379:Mice; D018482:Muscle, Skeletal / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D009206:Myocardium / Q000166:cytology / Q000378:metabolism*; D009474:Neurons / Q000187:drug effects / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D005680:gamma-Aminobutyric Acid
D000085:Acetates; D000588:Amines; C486058:Cacna2d2 protein, mouse; D015220:Calcium Channels; D003509:Cyclohexanecarboxylic Acids; D018691:Excitatory Amino Acid Antagonists; D005680:gamma-Aminobutyric Acid; D000077206:Gabapentin