{
  "abstract": "Cardiac G protein-gated inwardly rectifying potassium-K+ (GIRK) channels, formed by GIRK1/4 heterotetramers or GIRK4 homotetramers, are crucial regulators of heart rate, and their dysfunction is associated with atrial fibrillation. Despite their therapeutic potential as anti-arrhythmic targets, development of selective GIRK modulators has been limited by an incomplete understanding of their structures, gating mechanisms, and pharmacology. Here, we report high-resolution structures of the GIRK4 homotetramer and of GIRK1/4 heterotetramers, revealing that they form in unexpected 1:3 and 2:2 assembly stoichiometries that we corroborate using cell-based single molecule microscopy. Electrophysiological assays and molecular dynamics simulations further show that incorporation of one or two GIRK1 subunits into GIRK4-containing channels progressively opens the helix bundle crossing (HBC) gate and increases basal channel activity. Additional structures of GIRK1/4 complexes with ML297, a small-molecule ligand selective for GIRK1-containing channels, reveal distinct GIRK1-centered intersubunit binding environments. Remarkably, ML297 inhibits GIRK1/4 channels with a 1:3 stoichiometry but potentiates channels with a 2:2 stoichiometry, establishing a direct link between subunit composition, ligand-binding environment, and pharmacological efficacy. Together, these findings provide a structural and mechanistic framework for the rational design of ligands with enhanced selectivity among cardiac and neuronal GIRK channel heterotetramers.",
  "abstract_shown": true,
  "affiliations": [
    "St. Jude Children's Research Hospital"
  ],
  "article_type": "New results",
  "arxiv": null,
  "author_total": 15,
  "authors": [
    {
      "name": "L. Wang"
    },
    {
      "name": "T. Kawano"
    },
    {
      "name": "A. Santa-Cruz"
    },
    {
      "name": "N. Parvaiz"
    },
    {
      "name": "A. Zorn"
    },
    {
      "name": "Y. Lu"
    },
    {
      "name": "M. Zaka"
    },
    {
      "name": "N. Aly"
    },
    {
      "name": "J. Pentikis"
    },
    {
      "name": "E. Dadiotis"
    },
    {
      "name": "K. W. Chan"
    },
    {
      "name": "M. Cui"
    },
    {
      "name": "L. D. Plant"
    },
    {
      "name": "D. E. Logothetis"
    },
    {
      "affs": [
        0
      ],
      "name": "G. Skiniotis"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/fgpy19bj4maqd.bib",
  "cited_by": 0,
  "doi": "10.64898/2026.10.06.756879",
  "fulltext_url": "https://www.biorxiv.org/content/10.64898/2026.10.06.756879v1.full",
  "id": "fgpy19bj4maqd",
  "issns": [],
  "landing_url": "https://www.biorxiv.org/content/10.64898/2026.10.06.756879v1",
  "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",
      "molecular biology"
    ],
    [
      "openalex",
      "1312|Ion channel regulation and function"
    ]
  ],
  "openalex": "W7220849117",
  "pdf_url": "https://www.biorxiv.org/content/10.64898/2026.10.06.756879v1.full.pdf",
  "pmcid": null,
  "pmid": null,
  "published": "2026-10-06",
  "publisher": null,
  "ris": "https://research.draconitic.com/paper/fgpy19bj4maqd.ris",
  "sources": [
    {
      "first_seen": "2026-10-30T12:26:27Z",
      "native_id": "10.64898/2026.10.06.756879",
      "source": "biorxiv",
      "url": "https://www.biorxiv.org/content/10.64898/2026.10.06.756879v1"
    }
  ],
  "subjects": [
    {
      "field": "biochemistry",
      "origin": "biorxiv:molecular biology",
      "subfield": "molecular-biology"
    }
  ],
  "title": "Stoichiometry-dependent gating and structural pharmacology of cardiac GIRK1/4 channels",
  "title_text": "Stoichiometry-dependent gating and structural pharmacology of cardiac GIRK1/4 channels",
  "type": "preprint",
  "updated_at": "2026-10-30T12:26:27Z",
  "url": "https://research.draconitic.com/paper/fgpy19bj4maqd",
  "venue": "bioRxiv",
  "versions": []
}