{
  "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.",
  "abstract_shown": true,
  "affiliations": [
    "Northeastern University"
  ],
  "article_type": "New results",
  "arxiv": null,
  "author_total": 18,
  "authors": [
    {
      "name": "T. Kawano"
    },
    {
      "name": "L. Wang"
    },
    {
      "name": "K. W. Chan"
    },
    {
      "name": "A. Zorn"
    },
    {
      "name": "N. Parvaiz"
    },
    {
      "name": "M. Zaka"
    },
    {
      "name": "R. C. Kissell"
    },
    {
      "name": "C. Villalba-Galea"
    },
    {
      "name": "A. Santa-Cruz"
    },
    {
      "name": "Y. Lu"
    },
    {
      "name": "N. Aly"
    },
    {
      "name": "J. Pentikis"
    },
    {
      "name": "E. Dadiotis"
    },
    {
      "name": "S. Li"
    },
    {
      "name": "M. Cui"
    },
    {
      "name": "L. D. Plant"
    },
    {
      "name": "G. Skiniotis"
    },
    {
      "affs": [
        0
      ],
      "name": "D. E. Logothetis"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/0phzmcpgg2cc0.bib",
  "cited_by": 0,
  "doi": "10.64898/2026.10.06.756360",
  "fulltext_url": "https://www.biorxiv.org/content/10.64898/2026.10.06.756360v1.full",
  "id": "0phzmcpgg2cc0",
  "issns": [],
  "landing_url": "https://www.biorxiv.org/content/10.64898/2026.10.06.756360v1",
  "language": null,
  "licence": "CC-BY-NC-ND",
  "licence_label": "CC BY-NC-ND",
  "licence_source": "article",
  "licence_url": "https://creativecommons.org/licenses/by-nc-nd/4.0/",
  "metadata_licence": null,
  "native_subjects": [
    [
      "biorxiv",
      "biophysics"
    ],
    [
      "openalex",
      "1312|Ion channel regulation and function"
    ]
  ],
  "openalex": "W7220846128",
  "pdf_url": "https://www.biorxiv.org/content/10.64898/2026.10.06.756360v1.full.pdf",
  "pmcid": null,
  "pmid": null,
  "published": "2026-10-06",
  "publisher": null,
  "ris": "https://research.draconitic.com/paper/0phzmcpgg2cc0.ris",
  "sources": [
    {
      "first_seen": "2026-10-30T12:26:25Z",
      "native_id": "10.64898/2026.10.06.756360",
      "source": "biorxiv",
      "url": "https://www.biorxiv.org/content/10.64898/2026.10.06.756360v1"
    }
  ],
  "subjects": [
    {
      "field": "biochemistry",
      "origin": "biorxiv:biophysics",
      "subfield": "biophysics"
    }
  ],
  "title": "Asymmetric assembly underlies activation mechanism of neuronal GIRK1/2 channels",
  "title_text": "Asymmetric assembly underlies activation mechanism of neuronal GIRK1/2 channels",
  "type": "preprint",
  "updated_at": "2026-10-30T12:26:25Z",
  "url": "https://research.draconitic.com/paper/0phzmcpgg2cc0",
  "venue": "bioRxiv",
  "versions": []
}