• K J Alden and J García.
• Department of Physiology & Biophysics, University of Illinois at Chicago College of Medicine, Chicago, Illinois 60607, USA.
• J. Pharmacol. Exp. Ther. 2001 May 1;297(2):727-35.

AbstractCalcium 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.

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