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

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Abstract
Gabapentin is a clinically effective anticonvulsant with an unclear mechanism of action. It was described as a GABAB(1a,2) receptor subtype-selective agonist, activating postsynaptic K+ currents and inhibiting postsynaptic Ca2+ 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 Ca2+ channels targeted by gabapentin using whole-cell recording and multiphoton Ca2+ imaging. 1) We found that gabapentin and baclofen induced inwardly rectifying K+ currents (KGbp and KBac, respectively), sensitive to Ba2+ and Cs+. 2) A constitutively active KIR current, independent of GABAB receptor activation and sensitive to Ba2+ and Cs+ was also present. 3) KGbp, KBac, and KIR currents showed some differences in sensitivity to Ba2+ and Cs+, indicating the possible activation of distinct Kir3 currents, independent of KIR, by gabapentin and baclofen. 4) Gabapentin inhibition of Ca2+ channels was abolished by ω-conotoxin GVIA, but not by ω-agatoxin IVA and nimodipine, indicating a predominant action of gabapentin on N-type Ca2+ channels. 5) Gabapentin actions were linked to activation of pertussis toxin-sensitive G-proteins since N-ethylmaleimide (NEM) blocked KGbp activation and Ca2+ channel inhibition by gabapentin. 6) Finally, gabapentin reduced epileptiform discharges in slices via GABAB receptor activation. The anticonvulsant actions of gabapentin in hippocampal cells may thus involve GABAB receptor coupling to G-proteins and modulation of Kir3 and N-type Ca2+ channels. Moreover, gabapentin and baclofen activation of GABAB receptors may couple to distinct cellular targets. Synapse 50:95–109, 2003.