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Fibrosis and a unique pH landscape represent characteristic properties of the PDAC microenvironment. Mechanosensitive ion channels are involved in the activation of PSCs. Among these channels, K<jats:sub>2P<\/jats:sub>2.1 has not yet been studied in PSCs. K<jats:sub>2P<\/jats:sub>2.1 channels are pH- and mechanosensitive. We confirmed K<jats:sub>2P<\/jats:sub>2.1 expression in PSCs by RT-qPCR and immunofluorescence. PSCs from K<jats:sub>2P<\/jats:sub>2.1<jats:sup>+\/+<\/jats:sup> and K<jats:sub>2P<\/jats:sub>2.1<jats:sup>\u2212\/\u2212<\/jats:sup> mice were studied under conditions mimicking properties of the PDAC microenvironment (acidic extracellular pH (pH<jats:sub>e<\/jats:sub>), ambient pressure elevated by\u2009+\u2009100\u00a0mmHg). Migration and the cell area were taken as surrogates for PSC activation and evaluated with live cell imaging. pH<jats:sub>e<\/jats:sub>-dependent changes of the membrane potential of PSCs were investigated with DiBAC<jats:sub>4<\/jats:sub>(3), a voltage-sensitive fluorescent dye<jats:italic>.<\/jats:italic> We observed a correlation between morphological activation and progressive hyperpolarization of the cells in response to changes in pH<jats:sub>e<\/jats:sub> and pressure. The effect was in part dependent on the expression of K<jats:sub>2P<\/jats:sub>2.1 channels because the membrane potential of K<jats:sub>2P<\/jats:sub>2.1<jats:sup>+\/+<\/jats:sup> PSCs was always more hyperpolarized than that of K<jats:sub>2P<\/jats:sub>2.1<jats:sup>\u2212\/\u2212<\/jats:sup> PSCs. Cell migration velocity of K<jats:sub>2P<\/jats:sub>2.1<jats:sup>+\/+<\/jats:sup> cells decreased upon pressure application when cells were kept in an acidic medium (pH<jats:sub>e<\/jats:sub> 6.6). This was not the case in K<jats:sub>2P<\/jats:sub>2.1<jats:sup>\u2212\/\u2212<\/jats:sup> PSCs. Taken together, our study highlights the critical role of K<jats:sub>2P<\/jats:sub>2.1 channels in the combined sensing of environmental pressure and pH<jats:sub>e<\/jats:sub> by PSCs and in coordinating cellular morphology with membrane potential dynamics. Thus, K<jats:sub>2P<\/jats:sub>2.1 channels are important mechano-sensors in murine PSCs.<\/jats:p>","DOI":"10.1007\/s00424-024-03021-z","type":"journal-article","created":{"date-parts":[[2024,9,26]],"date-time":"2024-09-26T15:42:32Z","timestamp":1727365352000},"page":"147-157","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["K2P2.1 channels modulate the pH- and mechanosensitivity of pancreatic stellate cells"],"prefix":"10.1007","volume":"477","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3298-7351","authenticated-orcid":false,"given":"Micol","family":"Rugi","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Verena","family":"Hofschr\u00f6er","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7057-4761","authenticated-orcid":false,"given":"Zolt\u00e1n","family":"Peth\u0151","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Benjamin","family":"Soret","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1917-4214","authenticated-orcid":false,"given":"Thorsten","family":"Loeck","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Albrecht","family":"Schwab","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2024,9,26]]},"reference":[{"key":"3021_CR1","doi-asserted-by":"publisher","first-page":"459","DOI":"10.1101\/pdb.prot067702","volume":"2012","author":"DS Adams","year":"2012","unstructured":"Adams DS, Levin M (2012) Measuring resting membrane potential using the fluorescent voltage reporters DiBAC4(3) and CC2-DMPE. 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