Proper nerve cell communication is critical for brain function and depends on a delicate balance of excitatory and inhibitory signaling. Rapid excitatory signaling is mediated by excitatory ionotropic glutamate receptors, such as the NMDA (N-methyl-D-aspartate) and AMPA (α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid) receptors. Inhibitory signaling has fast and slow components, which are mediated by fast inhibitory currents through ionotropic GABAA-type and glycine receptors and slow inhibitory currents mediated by G protein-coupled receptors (GPCRs) and G-protein-gated inwardly rectifying potassium (GIRK or Kir3) channels. A large family of GPCRs, including those activated by GABA, DA, glutamate, serotonin, acetylcholine and opioids, directly couple to GIRK channels (Ehrengruber et al., 1997; Luscher et al., 1997; Scanziani, 2000; Wiser et al., 2006; Lujan et al., 2009). In addition, GIRK channels are regulated by interaction with neuronal proteins involved in protein trafficking (Lunn et al., 2007; Balana et al., 2013). GIRK channels allow potassium ions to flow into the cell better than out of the cell, a property referred to as “inward rectification.” The small outward current hyperpolarizes the cell's membrane potential, leading to inhibition of neuronal activity.
