GABA receptors in neocortical and hippocampal pyramidal neurons are coupled to different potassium channels.

Classically, GABA receptors are thought to regulate neuronal excitability via G-protein-coupled inwardly rectifying potassium (GIRK) channels. Recent data, however, indicate that GABA receptors can also activate two-pore domain potassium channels. Here, we investigate which potassium channels are coupled to GABA receptors in rat neocortical layer 5 and hippocampal CA1 pyramidal neurons. Bath application of the non-specific GIRK channel blocker barium (200 μm) abolished outward currents evoked by GABA receptors in CA1 pyramidal, but only partially blocked GABA responses in layer 5 neurons. Layer 5 and CA1 pyramidal neurons also showed differential sensitivity to tertiapin-Q, a specific GIRK channel blocker. Tertiapin-Q partially blocked GABA responses in CA1 pyramidal neurons, but was ineffective in blocking GABA responses in neocortical layer 5 neurons. Consistent with the idea that GABA receptors are coupled to two-pore domain potassium channels, the non-specific blockers quinidine and bupivacaine partially blocked GABA responses in both layer 5 and CA1 neurons. Finally, we show that lowering external pH, as occurs in hypoxia, blocks the component of GABA responses mediated by two-pore domain potassium channels in neocortical layer 5 pyramidal neurons, while at the same time revealing a GIRK channel component. These data indicate that GABA receptors in neocortical layer 5 and hippocampal CA1 pyramidal neurons are coupled to different channels, with this coupling pH dependent on neocortical layer 5 pyramidal neurons. This pH dependency may act to maintain constant levels of GABA inhibition during hypoxia by enhancing GIRK channel function following a reduction in two-pore domain potassium channel activity.