Differential Effect of Gabapentin on Neuronal and Muscle Calcium Currents
- Department of Physiology & Biophysics, University of Illinois at Chicago College of Medicine, Chicago, Illinois
Abstract
Calcium channels modulate cell function by controlling Ca2+influx. A main component of these proteins is the α2/δ 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 α2/δ subunit. Using the patch clamp technique, we tested the effects of GBP on Ca2+ 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 Ca2+ 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 Ca2+ currents at positive potentials. GBP did not reduce the low-voltage activated Ca2+ current under any experimental condition. Similar to DRG cells, GBP attenuated Ca2+ current in skeletal myotubes at positive membrane potentials in the presence of a depolarizing prepulse. However, GBP did not significantly alter Ca2+ currents in cardiac myocytes. Reverse transcription-polymerase chain reaction was used to confirm expression of the α2/δ subunit in these cells. Each cell type expressed multiple isoforms of α2/δ. Muscle cells showed a more variable expression of α2/δ subunits than did DRG cells. Our results suggest a possible participation of the α2/δ subunit in the action of GBP. Our data also indicate that GBP inhibits Ca2+ channels in a use- and voltage-dependent manner at a therapeutically relevant concentration.
Footnotes
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Send reprint requests to: Jesús Garcı́a, M.D., Ph.D., Department of Physiology & Biophysics, University of Illinois at Chicago College of Medicine, 900 S. Ashland Ave. M/C 902, Chicago, IL 60607. E-mail: garmar{at}uic.edu
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This work was supported by a grant from the National Science Foundation (J.G.). K.A. was partially supported by a training grant from the National Institutes of Health (T32 DK07739).
- Abbreviations:
- GBP
- gabapentin
- DRG
- dorsal root ganglion
- VGCC
- voltage-gated calcium channels
- LVA
- low-voltage activated
- HVA
- high-voltage activated
- I-V
- current-voltage
- RT-PCR
- reverse transcription-polymerase chain reaction
- PIPES
- 1,4-piperazinediethanesulfonic acid
- ANCOVA
- analysis of covariance
- τinactivation
- inactivation rate
- bp
- base pairs
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- Received September 21, 2000.
- Accepted January 26, 2001.
- The American Society for Pharmacology and Experimental Therapeutics
