(A) Cellular signaling pathway for the activation of a GIRK channel. A neurotransmitter (such as acetylcholine) binds to its receptor (GPCR), thus releasing the membrane-associated Gα and Gβγ subunits of a G-protein. The Gα subunit activates adenylate cyclase (AC) and phospholipase C (PLC), modulating the level of PIP2 in the cell membrane; the Gβγ subunit activates the GIRK channel. (B) The reduced systems studied by MacKinnon and co-workers are composed of lipid bilayers that contain a GIRK channel and ~1% of PIP2 lipid. The surface density of Gβγ subunits depends on the amount of Ni-NTA lipid in the bilayer because the Gβγ subunits (which are soluble) have a tag (His) that makes them bind to the Ni-NTA lipids. Image courtesy of Weiwei Wang.