Inhibition of the rat brain sodium channel Nav1.2 after prolonged exposure to gabapentin.
Prolonged exposure of neurons to gabapentin inhibits repetitive firing of Na(+)-dependent action potentials. Here, we studied the effect of such prolonged exposure to gabapentin on a rat sodium channel, Nav1.2. After 3 days of continuous incubation with gabapentin (10-1000 microM), Nav1.2 current density was decreased dose-dependently relative to untreated cells. The reduction was 57% at 30 microM gabapentin, while higher concentrations (100-1000 microM) did not result in greater effects. Prolonged treatment with gabapentin also caused the channel to inactivate at more hyperpolarized potentials. These effects provide a mechanistic basis for the inhibition of Na(+)-dependent repetitive firing upon prolonged exposure to gabapentin and may contribute to its anticonvulsant activity.
Liu
Yi
Y
Analgesics Drug Discovery, Johnson & Johnson Pharmaceutical Research & Development, Spring House, PA 19477-0776, USA. yliu10@prdus.jnj.com
Qin
Ning
N
Reitz
Tasha
T
Wang
Yan
Y
Flores
Christopher M
CM
D000200:Action Potentials / Q000187:drug effects; D000588:Amines / Q000494:pharmacology*; D000818:Animals; D000927:Anticonvulsants / Q000494:pharmacology*; D001921:Brain / Q000187:drug effects* / Q000502:physiology; D002460:Cell Line; D006224:Cricetinae; D003412:Cricetulus; D003509:Cyclohexanecarboxylic Acids / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D000077206:Gabapentin; D062551:NAV1.2 Voltage-Gated Sodium Channel; D009419:Nerve Tissue Proteins / Q000187:drug effects* / Q000502:physiology; D018408:Patch-Clamp Techniques; D051381:Rats; D015222:Sodium Channels / Q000187:drug effects* / Q000502:physiology; D005680:gamma-Aminobutyric Acid / Q000494:pharmacology*
D000588:Amines; D000927:Anticonvulsants; D003509:Cyclohexanecarboxylic Acids; D062551:NAV1.2 Voltage-Gated Sodium Channel; D009419:Nerve Tissue Proteins; C568253:Scn2A protein, rat; D015222:Sodium Channels; D005680:gamma-Aminobutyric Acid; D000077206:Gabapentin