ABSTRACT
G protein-gated inwardly rectifying potassium (GIRK) channels play important roles in controlling cellular excitability in the heart and brain. While structural data begin to unravel the molecular basis for G protein and alcohol dependent activation of GIRK channels, little is known about the modulation by cholesterol. Here, we present cryo-electron microscopy (cryoEM) structures of GIRK2 in the presence and absence of the cholesterol analog cholesteryl hemisuccinate (CHS), and PIP2. The structures and their comparison reveal that CHS binds near PIP2 in lipid-facing hydrophobic pockets of the transmembrane domain (TMD). CHS potentiates the effects of PIP2, which stabilizes the inter-domain region and promotes the engagement of the cytoplasmic domain (CTD) onto the transmembrane region. The results suggest that CHS acts as a positive allosteric modulator and identify novel therapeutic sites for modulating GIRK channels in the brain.
Competing Interest Statement
The authors have declared no competing interest.
Footnotes
Significance/Impact:
GIRK2 is one of the primary GIRK channels in brain. Characterization of cholesterol binding in GIRK2 provides new therapeutic sites for modulating these channels.
Many ion channels are modulated by cholesterol, but the molecular basis of this modulation has been elusive.
First cryoEM structures of pore-forming Kir alpha subunit.