Mammalian GIRK2-βγ G-protein complex
Figure: Overall structure of the GIRK- Gβγ complex.
a: Side view of the GIRK (blue), Gβ (red) and Gγ (green) complex. The front
Gβγ was removed for clarity. The extent of the phospholipid bilayer is shown by the black
lines. Other sites include the geranylgeranyl lipid modification at the Gγ C terminus ('gg'),
Na+ (purple), PIP2 (yellow) and K+ (green).
b: Top-down view of the complex from the membrane extracellular side.
[Figure reprinted by permission from Macmillan Publishers Ltd:
Nature, copyright 2013]
Rod MacKinnon group (The Rockefeller University)
The binding of an agonist, such as adrenaline,
acetylcholine, or glutamate, to a GPCR promotes the exchange of GDP for GTP
on a bound G protein, leading to the separate dissociation of the Gα
and Gβγ subunits from the receptor. The dissociated subunits then
initiate the signal transduction cascade by interacting with downstream
partners. Rod MacKinnon's group at the Rockefeller University determined the
structure of a G-protein-gated inward rectifier K+ (GIRK) channel
in complex with regulatory Gβγ subunits. GIRK channels mediate
cellular electrical excitability via neurotransmitter control. In cardiac
membranes, acetylcholine binding to the muscarinic acetylcholine receptor
initiates this cascade. Gβγ activates GIRK channels, causing them
to open, which drives the membrane voltage towards the resting potential and
slows membrane depolarization. In cardiac atrial pacemaker cells, this slows
the heart rate. The structure revealed one Gβγ protomer bound to
each subunit of the tetrameric ion channel, which was in a pre-open state
consistent with 'membrane delimited' activation of GIRK channels by G
proteins and the characteristic burst kinetics of channel gating. The
structure also revealed GIRK sites for the regulatory ligands
phosphatidylinositol-4,5-bisphosphate (PIP2) and Na+.
Whorton, MR, MacKinnon, R. X-ray structure of the mammalian GIRK2-[beta
gamma] G-protein complex, Nature 498, 190-197 (2013). DOI: