Asymmetric assembly underlies activation mechanism of neuronal GIRK1/2 channels
Kawano, T.; Wang, L.; Chan, K. W.; Zorn, A.; Parvaiz, N.; Zaka, M.; Kissell, R. C.; Villalba-Galea, C.; Santa-Cruz, A.; Lu, Y.; Aly, N.; Pentikis, J.; Dadiotis, E.; Li, S.; Cui, M.; Plant, L. D.; Skiniotis, G.; Logothetis, D. E.
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G protein-gated inwardly rectifying potassium (GIRK; Kir3) channels are principal effectors of inhibitory GPCR signaling. Here we combine cryo-electron microscopy, single-molecule imaging, electrophysiology and molecular dynamics to define the architecture and activation of neuronal GIRK1/2 channels. GIRK1/2 preferentially assembles as an asymmetric heterotetramer containing one GIRK1 and three GIRK2 subunits. Three PIP2; molecules bound to GIRK2 promote partial cytoplasmic-domain docking, whereas engagement of a fourth PIP2 by GIRK1 completes docking and opens the helix bundle crossing gate. GIRK1 also remodels the electrostatic environment beneath the selectivity filter, where its E141 and D173 residues create a permeation module that enhances K+ conduction. The GIRK1-selective activator ML297 binds at the GIRK1-GIRK2 interface and controls both permeation and gating. These findings establish how asymmetric assembly couples sequential lipid-dependent gating to efficient K+ permeation and GIRK1-dependent pharmacological activation.
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