GIRK channels provide a major pathway for inhibition in the brain that is important in both normal and diseased states. The canonical pathway for GIRK channel activation is mediated by G protein Gβγ subunits, which occurs following stimulation of a Gi/o-coupled GPCRs, such as GABAB, dopamine D2 or mu opioid receptors1, 2. Recent crystal structures of GIRK2 in complex with Gβγ and PIP2 have provided structural and mechanistic details of how Gβγ associates with GIRK channels15, 32. It has become increasingly evident that G protein-independent pathways also exist for modulating GIRK channels; however, much less is known about the mechanism of action. A majority of the identified compounds that modulate GIRK channels independently of G proteins appear to inhibit GIRK channel activity44–48. Conversely, the number of drugs that directly activate GIRK channels is small16, 17, 49, 50. Here, we demonstrate for the first time that ethanol and cholesterol directly activate GIRK2 channels via changes in the interaction with PIP2, and do not require the presence of G proteins or other endogenous proteins.
