Gabapentin actions on Kir3 currents and N‐type Ca 2+ channels via GABA B receptors in hippocampal pyramidal cells

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 ω‐conotoxin GVIA, but not by ω‐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. Synapse 50:95–109, 2003. © 2003 Wiley‐Liss, Inc.