{"entity": "researcher", "timestamp": "2026-08-20T21:23:18.751Z", "family": "Heusser", "given": "Stephanie A", "initials": "SA", "orcid": "0000-0003-3224-4547", "affiliations": ["Department of Biochemistry and Biophysics, Stockholm University, 11419 Stockholm, Sweden.", "Science for Life Laboratory, Stockholm University, 17165 Solna, Sweden."], "links": {"self": {"href": "https://publications-affiliated.scilifelab.se/researcher/d850b540ae3b408cbefb79c20b010a9a.json"}, "display": {"href": "https://publications-affiliated.scilifelab.se/researcher/d850b540ae3b408cbefb79c20b010a9a"}}, "publications": [{"entity": "publication", "iuid": "93fd95c94ec94e2eba303f9e4212c4c9", "links": {"self": {"href": "https://publications-affiliated.scilifelab.se/publication/93fd95c94ec94e2eba303f9e4212c4c9.json"}, "display": {"href": "https://publications-affiliated.scilifelab.se/publication/93fd95c94ec94e2eba303f9e4212c4c9"}}, "title": "Markov state models of proton- and pore-dependent activation in a pentameric ligand-gated ion channel.", "authors": [{"family": "Bergh", "given": "Cathrine", "initials": "C", "orcid": "0000-0001-7540-5887", "researcher": {"href": "https://publications-affiliated.scilifelab.se/researcher/5c8a3efa976b41edb6ace4efae952125.json"}}, {"family": "Heusser", "given": "Stephanie A", "initials": "SA", "orcid": "0000-0003-3224-4547", "researcher": {"href": "https://publications-affiliated.scilifelab.se/researcher/d850b540ae3b408cbefb79c20b010a9a.json"}}, {"family": "Howard", "given": "Rebecca", "initials": "R"}, {"family": "Lindahl", "given": "Erik", "initials": "E", "orcid": "0000-0002-2734-2794", "researcher": {"href": "https://publications-affiliated.scilifelab.se/researcher/9eb30fa60f9b4b95842ac9d9f3a0eaa9.json"}}], "type": "journal article", "published": "2021-10-15", "journal": {"title": "Elife", "issn": "2050-084X", "volume": "10", "issn-l": "2050-084X"}, "abstract": "Ligand-gated ion channels conduct currents in response to chemical stimuli, mediating electrochemical signaling in neurons and other excitable cells. For many channels, the details of gating remain unclear, partly due to limited structural data and simulation timescales. Here, we used enhanced sampling to simulate the pH-gated channel GLIC, and construct Markov state models (MSMs) of gating. Consistent with new functional recordings, we report in oocytes, our analysis revealed differential effects of protonation and mutation on free-energy wells. Clustering of closed- versus open-like states enabled estimation of open probabilities and transition rates, while higher-order clustering affirmed conformational trends in gating. Furthermore, our models uncovered state- and protonation-dependent symmetrization. This demonstrates the applicability of MSMs to map energetic and conformational transitions between ion-channel functional states, and how they reproduce shifts upon activation or mutation, with implications for modeling neuronal function and developing state-selective drugs.", "doi": "10.7554/eLife.68369", "pmid": "34652272", "labels": [], "xrefs": [{"db": "pmc", "key": "PMC8635979"}, {"db": "pii", "key": "68369"}], "notes": [], "created": "2026-08-20T13:53:46.502Z", "modified": "2026-08-20T13:53:46.591Z"}, {"entity": "publication", "iuid": "b78f0d3a0ba7431ba0d9e6aca153f29a", "links": {"self": {"href": "https://publications-affiliated.scilifelab.se/publication/b78f0d3a0ba7431ba0d9e6aca153f29a.json"}, "display": {"href": "https://publications-affiliated.scilifelab.se/publication/b78f0d3a0ba7431ba0d9e6aca153f29a"}}, "title": "Author response: Markov state models of proton- and pore-dependent activation in a pentameric ligand-gated ion channel", "authors": [{"family": "Bergh", "given": "Cathrine", "initials": "C", "orcid": "0000-0001-7540-5887", "researcher": {"href": "https://publications-affiliated.scilifelab.se/researcher/5c8a3efa976b41edb6ace4efae952125.json"}}, {"family": "Heusser", "given": "Stephanie A", "initials": "SA", "orcid": "0000-0003-3224-4547", "researcher": {"href": "https://publications-affiliated.scilifelab.se/researcher/d850b540ae3b408cbefb79c20b010a9a.json"}}, {"family": "Howard", "given": "Rebecca", "initials": "R"}, {"family": "Lindahl", "given": "Erik", "initials": "E", "orcid": "0000-0002-2734-2794", "researcher": {"href": "https://publications-affiliated.scilifelab.se/researcher/9eb30fa60f9b4b95842ac9d9f3a0eaa9.json"}}], "type": "peer-review", "published": "2021-10-01", "journal": {"issn-l": null}, "abstract": null, "doi": "10.7554/elife.68369.sa2", "pmid": null, "labels": [], "xrefs": [], "notes": [], "created": "2026-08-20T13:53:48.370Z", "modified": "2026-08-20T13:53:48.431Z"}, {"entity": "publication", "iuid": "39115549ae2445cfbc8ce863fe090a2f", "links": {"self": {"href": "https://publications-affiliated.scilifelab.se/publication/39115549ae2445cfbc8ce863fe090a2f.json"}, "display": {"href": "https://publications-affiliated.scilifelab.se/publication/39115549ae2445cfbc8ce863fe090a2f"}}, "title": "Markov State Models of Proton- and Gate-Dependent Activation in a Pentameric Ligand-Gated Ion Channel", "authors": [{"family": "Bergh", "given": "Cathrine", "initials": "C", "orcid": "0000-0001-7540-5887", "researcher": {"href": "https://publications-affiliated.scilifelab.se/researcher/5c8a3efa976b41edb6ace4efae952125.json"}}, {"family": "Heusser", "given": "Stephanie A", "initials": "SA", "orcid": "0000-0003-3224-4547", "researcher": {"href": "https://publications-affiliated.scilifelab.se/researcher/d850b540ae3b408cbefb79c20b010a9a.json"}}, {"family": "Howard", "given": "Rebecca J", "initials": "RJ", "orcid": "0000-0003-2049-3378", "researcher": {"href": "https://publications-affiliated.scilifelab.se/researcher/5ce04593b5b24aaa8978fda1447dd0bf.json"}}, {"family": "Lindahl", "given": "Erik", "initials": "E", "orcid": "0000-0002-2734-2794", "researcher": {"href": "https://publications-affiliated.scilifelab.se/researcher/9eb30fa60f9b4b95842ac9d9f3a0eaa9.json"}}], "type": "posted-content", "published": "2021-03-12", "journal": {"issn-l": null}, "abstract": null, "doi": "10.1101/2021.03.12.435097", "pmid": null, "labels": [], "xrefs": [], "notes": [], "created": "2026-08-20T10:03:09.282Z", "modified": "2026-08-20T10:03:09.324Z"}, {"entity": "publication", "iuid": "b09dfa4993534da1a485d5cc0783db9d", "links": {"self": {"href": "https://publications-affiliated.scilifelab.se/publication/b09dfa4993534da1a485d5cc0783db9d.json"}, "display": {"href": "https://publications-affiliated.scilifelab.se/publication/b09dfa4993534da1a485d5cc0783db9d"}}, "title": "Allosteric potentiation of a ligand-gated ion channel is mediated by access to a deep membrane-facing cavity.", "authors": [{"family": "Heusser", "given": "Stephanie A", "initials": "SA", "orcid": "0000-0003-3224-4547", "researcher": {"href": "https://publications-affiliated.scilifelab.se/researcher/d850b540ae3b408cbefb79c20b010a9a.json"}}, {"family": "Lycksell", "given": "Marie", "initials": "M"}, {"family": "Wang", "given": "Xueqing", "initials": "X"}, {"family": "McComas", "given": "Sarah E", "initials": "SE"}, {"family": "Howard", "given": "Rebecca J", "initials": "RJ"}, {"family": "Lindahl", "given": "Erik", "initials": "E"}], "type": "journal article", "published": "2018-10-16", "journal": {"title": "Proc. Natl. Acad. Sci. U.S.A.", "issn": "1091-6490", "volume": "115", "issue": "42", "pages": "10672-10677", "issn-l": "0027-8424"}, "abstract": "Theories of general anesthesia have shifted in focus from bulk lipid effects to specific interactions with membrane proteins. Target receptors include several subtypes of pentameric ligand-gated ion channels; however, structures of physiologically relevant proteins in this family have yet to define anesthetic binding at high resolution. Recent cocrystal structures of the bacterial protein GLIC provide snapshots of state-dependent binding sites for the common surgical agent propofol (PFL), offering a detailed model system for anesthetic modulation. Here, we combine molecular dynamics and oocyte electrophysiology to reveal differential motion and modulation upon modification of a transmembrane binding site within each GLIC subunit. WT channels exhibited net inhibition by PFL, and a contraction of the cavity away from the pore-lining M2 helix in the absence of drug. Conversely, in GLIC variants exhibiting net PFL potentiation, the cavity was persistently expanded and proximal to M2. Mutations designed to favor this deepened site enabled sensitivity even to subclinical concentrations of PFL, and a uniquely prolonged mode of potentiation evident up to \u223c30 min after washout. Dependence of these prolonged effects on exposure time implicated the membrane as a reservoir for a lipid-accessible binding site. However, at the highest measured concentrations, potentiation appeared to be masked by an acute inhibitory effect, consistent with the presence of a discrete, water-accessible site of inhibition. These results support a multisite model of transmembrane allosteric modulation, including a possible link between lipid- and receptor-based theories that could inform the development of new anesthetics.", "doi": "10.1073/pnas.1809650115", "pmid": "30275330", "labels": [], "xrefs": [{"db": "pmc", "key": "PMC6196478"}, {"db": "pii", "key": "1809650115"}], "notes": [], "created": "2026-08-20T09:29:50.987Z", "modified": "2026-08-20T09:29:51.061Z"}]}