Breton, Jean-DidierStuart, Greg2021-06-280953-816Xhttp://hdl.handle.net/1885/238281Classically, GABAB receptors are thought to regulate neuronal excitability via G-protein-coupled inwardly rectifying potassium (GIRK) channels. Recent data, however, indicate that GABAB receptors can also activate two-pore domain potassium channels. Here, we investigate which potassium channels are coupled to GABAB 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 GABAB receptors in CA1 pyramidal, but only partially blocked GABAB 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 GABAB responses in CA1 pyramidal neurons, but was ineffective in blocking GABAB responses in neocortical layer 5 neurons. Consistent with the idea that GABAB receptors are coupled to two-pore domain potassium channels, the non-specific blockers quinidine and bupivacaine partially blocked GABAB responses in both layer 5 and CA1 neurons. Finally, we show that lowering external pH, as occurs in hypoxia, blocks the component of GABAB 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 GABAB 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 GABAB inhibition during hypoxia by enhancing GIRK channel function following a reduction in two-pore domain potassium channel activity.This work is supported by the National Health and Medical Research Council of Australia (APP1009425) and the Australian Research Council Centre of Excellence for Integrative Brain Function (CE140100007).application/pdfen-AU© 2017 Federation of European Neuroscience Societies and John Wiley & Sons LtdcortexGABAinhibitionsynapsevoltage clamp201710.1111/ejn.137772020-11-23