Activation of GABAB receptors leads to opening of GIRK channels. Primarily three different GIRK channels exist in the mammalian brain (GIRK1-3) that assemble into homo-tetramers (GIRK2) or hetero-tetramers (GIRK1/2, GIRK1/3, and GIRK2/3) [3]. GIRK channels preferentially allow K+ ions to enter the neuron (referred to as inward rectification). However, the small outward flow of K+ ions is of physiological relevance because it reduces the excitability of neurons. Stimulation of GPCRs that communicate through pertussis toxin (PTX)-sensitive G-proteins (the Gi/o family), such as the GABAB receptor, activates GIRK channels through the direct binding of G-protein Gβγ dimers to the channel [3]. More recent evidence suggests the PTX-sensitive Gα subunits also associate directly with the channel, suggesting the inactive heterotrimer is situated near the channel forming a signaling complex [4,5] (Figure 1). In summary, GIRK channels contribute to the resting membrane potential of neurons and, upon receptor stimulation, generate a hyperpolarizing postsynaptic potential [3].
