{"entity": "publication", "iuid": "2e5eb75831a14ba8b151d1e29a23e257", "timestamp": "2026-10-04T21:04:42.867Z", "links": {"self": {"href": "https://publications-affiliated.scilifelab.se/publication/2e5eb75831a14ba8b151d1e29a23e257.json"}, "display": {"href": "https://publications-affiliated.scilifelab.se/publication/2e5eb75831a14ba8b151d1e29a23e257"}}, "title": "Structure and electromechanical coupling of a voltage-gated Na+/H+ exchanger.", "authors": [{"family": "Yeo", "given": "Hyunku", "initials": "H", "orcid": "0000-0002-8701-8902", "researcher": {"href": "https://publications-affiliated.scilifelab.se/researcher/1a54fc6a8f4645279adee47f0133b6be.json"}}, {"family": "Mehta", "given": "Ved", "initials": "V", "orcid": "0000-0002-3459-4404", "researcher": {"href": "https://publications-affiliated.scilifelab.se/researcher/e1ba0a603f10431ebbb474b3821ce287.json"}}, {"family": "Gulati", "given": "Ashutosh", "initials": "A", "orcid": "0000-0003-0960-994X", "researcher": {"href": "https://publications-affiliated.scilifelab.se/researcher/084ce4065c7d4172969dd9aa2600790b.json"}}, {"family": "Drew", "given": "David", "initials": "D", "orcid": "0000-0001-8866-6349", "researcher": {"href": "https://publications-affiliated.scilifelab.se/researcher/e80593c5f1ec4f87a38b079e5909f0b0.json"}}], "type": "journal article", "published": "2023-11-00", "journal": {"title": "Nature", "issn": "1476-4687", "volume": "623", "issue": "7985", "pages": "193-201", "issn-l": "0028-0836"}, "abstract": "Voltage-sensing domains control the activation of voltage-gated ion channels, with a few exceptions1. One such exception is the sperm-specific Na+/H+ exchanger SLC9C1, which is the only known transporter to be regulated by voltage-sensing domains2-5. After hyperpolarization of sperm flagella, SLC9C1 becomes active, causing pH alkalinization and CatSper Ca2+ channel activation, which drives chemotaxis2,6. SLC9C1 activation is further regulated by cAMP2,7, which is produced by soluble adenyl cyclase (sAC). SLC9C1 is therefore an essential component of the pH-sAC-cAMP signalling pathway in metazoa8,9, required for sperm motility and fertilization4. Despite its importance, the molecular basis of SLC9C1 voltage activation is unclear. Here we report cryo-electron microscopy (cryo-EM) structures of sea urchin SLC9C1 in detergent and nanodiscs. We show that the voltage-sensing domains are positioned in an unusual configuration, sandwiching each side of the SLC9C1 homodimer. The S4 segment is very long, 90 \u00c5 in length, and connects the voltage-sensing domains to the cytoplasmic cyclic-nucleotide-binding domains. The S4 segment is in the up configuration-the inactive state of SLC9C1. Consistently, although a negatively charged cavity is accessible for Na+ to bind to the ion-transporting domains of SLC9C1, an intracellular helix connected to S4 restricts their movement. On the basis of the differences in the cryo-EM structure of SLC9C1 in the presence of cAMP, we propose that, upon hyperpolarization, the S4 segment moves down, removing this constriction and enabling Na+/H+ exchange.", "doi": "10.1038/s41586-023-06518-2", "pmid": "37880360", "labels": [], "xrefs": [{"db": "pmc", "key": "PMC10620092"}, {"db": "pii", "key": "10.1038/s41586-023-06518-2"}], "notes": [], "created": "2026-09-23T09:03:34.761Z", "modified": "2026-09-23T09:03:34.921Z"}