Gabapentin actions on Kir3 currents and N-type Ca2+ channels via GABAB receptors in hippocampal pyramidal cells.
Synapse. 2003-08-11; 50(2): 95-109
DOI: 10.1002/syn.10247
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1. Synapse. 2003 Nov;50(2):95-109.
Gabapentin actions on Kir3 currents and N-type Ca2+ channels via GABAB receptors
in hippocampal pyramidal cells.
Bertrand S(1), Nouel D, Morin F, Nagy F, Lacaille JC.
Author information:
(1)Département de Physiologie et Centre de Recherche en Sciences Neurologiques,
Université de Montréal, Montréal, Québec, Canada.
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.
Copyright 2003 Wiley-Liss, Inc.
DOI: 10.1002/syn.10247
PMID: 12923812 [Indexed for MEDLINE]