Several modulators have been described that alter GIRK channel activity, including Na+44,45, ethanol46-48 and phosphorylation by PKA49,50 and PKC kinases51-57. Both Na+ and ethanol appear to stimulate GIRK channels through a specific binding site on the channel (Figure 2, see below). PKC-dependent phosphorylation decreases while PKA-dependent phosphorylation enhances channel activity49-57 (Figure 2C). In addition to these modulators, changes in the levels of the membrane phospholipid phosphatidylinositol 4,5 bisphosphate (PIP2), can regulate the activity of GIRK channels58-60. Stimulation of GPCRs that couple to Gq G proteins stimulate phospholipase C (PLC) and deplete plasma membrane levels of PIP2, leading to desensitizing GIRK currents 55,61,62 (but see ref63). Activation of PLC also leads to stimulation of PKC, enabling cross-talk of these two pathways (PIP2 depletion and PKC phosphorylation) in the regulation of GIRK channels55,56.
