Gabapentin actions on Kir3 currents and N-type Ca2+ channels via GABAB receptors in hippocampal pyramidal cells

Synapse. 2003 Nov;50(2):95-109. doi: 10.1002/syn.10247.


Gabapentin is a clinically effective anticonvulsant with an unclear mechanism of action. It was described as a GABA(B(1a,2)) receptor subtype-selective agonist, activating postsynaptic K(+) currents and inhibiting postsynaptic Ca(2+) channels in CA1 pyramidal cells, but without presynaptic actions. These activities appeared controversial and we therefore sought to further clarify gabapentin actions in rat hippocampal slices by characterizing K(+) currents and Ca(2+) channels targeted by gabapentin using whole-cell recording and multiphoton Ca(2+) imaging. 1) We found that gabapentin and baclofen induced inwardly rectifying K(+) currents (K(Gbp) and K(Bac), respectively), sensitive to Ba(2+) and Cs(+). 2) A constitutively active K(IR) current, independent of GABA(B) receptor activation and sensitive to Ba(2+) and Cs(+) was also present. 3) K(Gbp), K(Bac), and K(IR) currents showed some differences in sensitivity to Ba(2+) and Cs(+), indicating the possible activation of distinct Kir3 currents, independent of K(IR), by gabapentin and baclofen. 4) Gabapentin inhibition of Ca(2+) channels was abolished by omega-conotoxin GVIA, but not by omega-agatoxin IVA and nimodipine, indicating a predominant action of gabapentin on N-type Ca(2+) channels. 5) Gabapentin actions were linked to activation of pertussis toxin-sensitive G-proteins since N-ethylmaleimide (NEM) blocked K(Gbp) activation and Ca(2+) channel inhibition by gabapentin. 6) Finally, gabapentin reduced epileptiform discharges in slices via GABA(B) receptor activation. The anticonvulsant actions of gabapentin in hippocampal cells may thus involve GABA(B) receptor coupling to G-proteins and modulation of Kir3 and N-type Ca(2+) channels. Moreover, gabapentin and baclofen activation of GABA(B) receptors may couple to distinct cellular targets.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acetates / pharmacology*
  • Action Potentials / drug effects
  • Action Potentials / physiology
  • Amines*
  • Animals
  • Anticonvulsants / pharmacology*
  • Baclofen / pharmacology
  • Barium / pharmacology
  • Calcium Channel Blockers / pharmacology
  • Calcium Channels, N-Type / drug effects*
  • Calcium Channels, N-Type / metabolism
  • Cell Membrane / drug effects
  • Cell Membrane / metabolism
  • Cesium / pharmacology
  • Cyclohexanecarboxylic Acids*
  • Epilepsy / drug therapy
  • Epilepsy / metabolism
  • Epilepsy / physiopathology
  • Ethylmaleimide / pharmacology
  • G Protein-Coupled Inwardly-Rectifying Potassium Channels
  • GTP-Binding Proteins / drug effects
  • GTP-Binding Proteins / metabolism
  • Gabapentin
  • Hippocampus / cytology
  • Hippocampus / drug effects*
  • Hippocampus / metabolism
  • Male
  • Organ Culture Techniques
  • Potassium Channels / drug effects*
  • Potassium Channels / metabolism
  • Potassium Channels, Inwardly Rectifying*
  • Pyramidal Cells / drug effects*
  • Pyramidal Cells / metabolism
  • Rats
  • Rats, Sprague-Dawley
  • Receptors, GABA-B / drug effects*
  • Receptors, GABA-B / metabolism
  • gamma-Aminobutyric Acid*
  • omega-Conotoxin GVIA / pharmacology


  • Acetates
  • Amines
  • Anticonvulsants
  • Calcium Channel Blockers
  • Calcium Channels, N-Type
  • Cyclohexanecarboxylic Acids
  • G Protein-Coupled Inwardly-Rectifying Potassium Channels
  • Potassium Channels
  • Potassium Channels, Inwardly Rectifying
  • Receptors, GABA-B
  • Cesium
  • Barium
  • gamma-Aminobutyric Acid
  • Gabapentin
  • omega-Conotoxin GVIA
  • GTP-Binding Proteins
  • Baclofen
  • Ethylmaleimide