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Approximately 70 genes encode VGKC alpha subunits, which assemble into functional tetrameric channel complexes. These subunits can also combine to form heteromeric channels, significantly expanding the potential diversity of VGKCs. The functional expression and physiological role of heteromeric K-channels have remained largely unexplored due to the lack of tools to probe their functions. Conotoxins, from predatory cone snails, have high affinity and specificity for heteromeric combinations of K-channels and show great promise for defining their physiological roles. In this work, using conotoxin <jats:sc>k<\/jats:sc>M-RIIIJ as a pharmacological probe, we explore the expression and physiological functions of heteromeric K<jats:sub>v<\/jats:sub>1.2 channels using constellation pharmacology platform. We report that heteromers of K<jats:sub>v<\/jats:sub>1.2\/1.1 are highly expressed in proprioceptive neurons found in the dorsal root ganglion (DRG). Inhibition of K<jats:sub>v<\/jats:sub>1.2\/1.1 heteromers leads to an influx of calcium ions, suggesting that these channels regulate neuronal excitability. We also present evidence that K<jats:sub>v<\/jats:sub>1.2\/1.1 heteromers counteract persistent sodium currents, and that inhibiting these channels leads to tonic firing of action potentials. Additionally, <jats:sc>k<\/jats:sc>M-RIIIJ impaired proprioception in mice, uncovering a previously unrecognized physiological function of heteromeric K<jats:sub>v<\/jats:sub>1.2\/1.1 channels in proprioceptive sensory neurons of the DRG.<\/jats:p>","DOI":"10.1038\/s41598-024-82165-5","type":"journal-article","created":{"date-parts":[[2024,12,28]],"date-time":"2024-12-28T03:30:21Z","timestamp":1735356621000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Conotoxin kM-RIIIJ reveals interplay between Kv1-channels and persistent sodium currents in proprioceptive DRG neurons"],"prefix":"10.1038","volume":"14","author":[{"given":"Shrinivasan","family":"Raghuraman","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jackson","family":"Carter","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Markel","family":"Walter","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Manju","family":"Karthikeyan","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kevin","family":"Chase","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mat\u00edas L.","family":"Giglio","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mario","family":"Giacobassi","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Russell W.","family":"Teichert","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Heinrich","family":"Terlau","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Baldomero M.","family":"Olivera","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2024,12,28]]},"reference":[{"key":"82165_CR1","unstructured":"Hille, B., Ion Channels of Excitable Membranes. 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