{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,12]],"date-time":"2026-04-12T07:40:59Z","timestamp":1775979659265,"version":"3.50.1"},"reference-count":51,"publisher":"Wiley","issue":"2","license":[{"start":{"date-parts":[[2018,12,11]],"date-time":"2018-12-11T00:00:00Z","timestamp":1544486400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/501100000024","name":"Canadian Institutes of Health Research","doi-asserted-by":"publisher","award":["MOP 142469"],"award-info":[{"award-number":["MOP 142469"]}],"id":[{"id":"10.13039\/501100000024","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["physoc.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Experimental Physiology"],"published-print":{"date-parts":[[2019,2]]},"abstract":"<jats:sec><jats:title>New Findings<\/jats:title><jats:p><jats:list list-type=\"bullet\">\n<jats:list-item><jats:p><jats:bold>What is the central question of this study?<\/jats:bold><\/jats:p>\n<jats:p>The mammalian carotid body (CB) is a peripheral chemoreceptor organ involved in O<jats:sub>2<\/jats:sub> and CO<jats:sub>2<\/jats:sub>\/H<jats:sup>+<\/jats:sup> homeostasis. Recent studies suggest that 5\u2010HT, released from CB receptor cells, can stimulate adjacent glial\u2010like type\u00a0II cells, leading to an increase in intracellular Ca<jats:sup>2+<\/jats:sup> (\u0394[Ca<jats:sup>2+<\/jats:sup>]<jats:sub>i<\/jats:sub>) and activation of ATP\u2010permeable pannexin\u20101 (Panx\u20101) channels. The aim of this study was to elucidate the role of protein kinases in the 5\u2010HT\u2013[Ca<jats:sup>2+<\/jats:sup>]<jats:sub>i<\/jats:sub>\u2013Panx\u20101 signalling pathway.<\/jats:p>\n<\/jats:list-item>\n<jats:list-item><jats:p><jats:bold>What is the main finding and its importance?<\/jats:bold><\/jats:p>\n<jats:p>Src family kinase and protein kinase\u00a0A, acting downstream from \u0394[Ca<jats:sup>2+<\/jats:sup>]<jats:sub>i<\/jats:sub>, played central roles in 5\u2010HT\u2010mediated Panx\u20101 channel activation. This provides new insight into mechanisms regulating CB excitation, especially in pathophysiological conditions.<\/jats:p>\n<\/jats:list-item>\n<\/jats:list><\/jats:p><\/jats:sec><jats:sec><jats:title>Abstract<\/jats:title><jats:p>Chemoreceptor (type\u00a0I) cells of the rodent carotid body (CB) synthesize and release several neurotransmitters\/neuromodulators, including 5\u2010hydroxytryptamine (5\u2010HT), implicated in enhanced CB excitation after exposure to chronic intermittent hypoxia, e.g. sleep apnoea. However, recent studies suggest that 5\u2010HT can robustly stimulate adjacent glial\u2010like type\u00a0II cells via ketanserin\u2010sensitive 5\u2010HT<jats:sub>2<\/jats:sub> receptors, leading to intracellular Ca<jats:sup>2+<\/jats:sup> elevation (\u0394[Ca<jats:sup>2+<\/jats:sup>]<jats:sub>i<\/jats:sub>) and activation of ATP\u2010permeable pannexin\u20101 (Panx\u20101) channels. Using dissociated rat CB cultures, we investigated the role of protein kinases in the intracellular signalling pathways in type\u00a0II cells. In isolated type\u00a0II cells, 5\u2010HT activated a Panx\u20101\u2010like inward current (<jats:italic>I<\/jats:italic><jats:sub>5\u2010HT<\/jats:sub>) that was reversibly inhibited by the Src family kinase inhibitor PP2 (1\u00a0\u03bc<jats:sc>m<\/jats:sc>), but not by its inactive analogue, PP3 (1\u00a0\u03bc<jats:sc>m<\/jats:sc>). Moreover, <jats:italic>I<\/jats:italic><jats:sub>5\u2010HT<\/jats:sub> was reversibly inhibited (&gt;90%) by H89 (1\u00a0\u03bc<jats:sc>m<\/jats:sc>), a protein kinase\u00a0A blocker, whereas the protein kinase\u00a0C blocker GF109203X (2\u00a0\u03bc<jats:sc>m<\/jats:sc>) was largely ineffective. In contrast, the P2Y2R agonist UTP (100\u00a0\u03bc<jats:sc>m<\/jats:sc>) activated Panx\u20101\u2010like currents that were reversibly inhibited (\u223c60%) by either H89 or GF109203X. Using fura\u20102 spectrofluorimetry, the 5\u2010HT\u2010induced \u0394[Ca<jats:sup>2+<\/jats:sup>]<jats:sub>i<\/jats:sub> was unaffected by PP2, H89 and GF109293X, suggesting that the kinases acted downstream of the Ca<jats:sup>2+<\/jats:sup> rise. Given that intracellular Ca<jats:sup>2+<\/jats:sup> chelation was previously shown to block receptor\u2010mediated Panx\u20101 current activation in type\u00a0II cells, these data suggest that CB neuromodulators use overlapping, but not necessarily identical, signalling pathways to activate Panx\u20101 channels and release ATP, a CB excitatory neurotransmitter. In conclusion, these studies provide new mechanistic insight into 5\u2010HT signalling in the CB that has pathophysiological relevance.<\/jats:p><\/jats:sec>","DOI":"10.1113\/ep087411","type":"journal-article","created":{"date-parts":[[2018,11,20]],"date-time":"2018-11-20T09:39:56Z","timestamp":1542706796000},"page":"244-253","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Evidence for protein kinase involvement in the 5\u2010HT\u2013[Ca<sup>2+<\/sup>]<sub>i<\/sub>\u2013pannexin\u20101 signalling pathway in type II glial cells of the rat carotid body"],"prefix":"10.1113","volume":"104","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-5113-5437","authenticated-orcid":false,"given":"Erin M.","family":"Leonard","sequence":"first","affiliation":[{"name":"Department of Biology McMaster University  Hamilton Ontario 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