Activation of postsynaptic GABAB receptors115, D2 receptors116 and group II metabotropic glutamate receptors mGluRs117 by transmitters released from neighboring neurons (synaptic transmission) may also activate GIRK channels. For GABAergic synapses, GABA released spontaneously or driven by a single action potential produces a fast inhibitory postsynaptic potential, mediated by GABAA channels (Figure 1C - left panel, 3B). By contrast, strong or repetitive stimulation is required to elicit the slow inhibitory potential, suggesting that GABA released into the synaptic cleft diffuses and activates peri-synaptic GABAB receptors coupled to GIRK channels (Figure 1C-right panel, 3B)118-120. Thus, GABAB receptors/GIRK channels could be positioned directly adjacent to synaptically localized GABAA receptors or in a neighboring dendritic spine (for review, see ref121). The slow time course of outward current through GIRK channels therefore correlates with the time required for diffusion of the neurotransmitter and is not limited by the speed of G protein activation. The reuptake/degradation of the neurotransmitter and the limited space for diffusion may affect the amplitude of the slow IPSC, thus regulating the degree of inhibition. In the hippocampus, generation of the slow
