Asymmetric assembly underlies activation mechanism of neuronal GIRK1/2 channels
- 1Northeastern University
Abstract
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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BibTeX
@misc{kawano2026asymmetric,
title = {{Asymmetric assembly underlies activation mechanism of neuronal GIRK1/2 channels}},
author = {T. Kawano and L. Wang and K. W. Chan and A. Zorn and N. Parvaiz and M. Zaka and R. C. Kissell and C. Villalba-Galea and A. Santa-Cruz and Y. Lu and N. Aly and J. Pentikis and E. Dadiotis and S. Li and M. Cui and L. D. Plant and G. Skiniotis and D. E. Logothetis},
howpublished = {bioRxiv},
year = {2026},
month = oct,
doi = {10.64898/2026.10.06.756360},
url = {https://www.biorxiv.org/content/10.64898/2026.10.06.756360v1},
note = {CC BY-NC-ND},
}
RIS
TY - UNPB
TI - Asymmetric assembly underlies activation mechanism of neuronal GIRK1/2 channels
AU - T. Kawano
AU - L. Wang
AU - K. W. Chan
AU - A. Zorn
AU - N. Parvaiz
AU - M. Zaka
AU - R. C. Kissell
AU - C. Villalba-Galea
AU - A. Santa-Cruz
AU - Y. Lu
AU - N. Aly
AU - J. Pentikis
AU - E. Dadiotis
AU - S. Li
AU - M. Cui
AU - L. D. Plant
AU - G. Skiniotis
AU - D. E. Logothetis
PY - 2026
DA - 2026/10/06
PB - bioRxiv
DO - 10.64898/2026.10.06.756360
UR - https://www.biorxiv.org/content/10.64898/2026.10.06.756360v1
AB - 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.
ER -