{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,12]],"date-time":"2026-04-12T12:40:54Z","timestamp":1775997654423,"version":"3.50.1"},"reference-count":47,"publisher":"Wiley","issue":"15","license":[{"start":{"date-parts":[[2017,9,21]],"date-time":"2017-09-21T00:00:00Z","timestamp":1505952000000},"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":[],"crossmark-restriction":false},"short-container-title":["The Journal of Physiology"],"published-print":{"date-parts":[[2018,8]]},"abstract":"<jats:sec><jats:title>Key points<\/jats:title><jats:p><jats:list list-type=\"bullet\">\n<jats:list-item><jats:p>Adenosine and dopamine (DA) are neuromodulators in the carotid body (CB) chemoafferent pathway, but their mechanisms of action are incompletely understood.<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>Using functional co\u2010cultures of rat CB chemoreceptor (type I) cells and sensory petrosal neurons (PNs), we show that adenosine enhanced a hyperpolarization\u2010activated cation current <jats:italic>I<\/jats:italic><jats:sub>h<\/jats:sub> in chemosensory PNs via A2a receptors, whereas DA had the opposite effect via D2 receptors.<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>Adenosine caused a depolarizing shift in the <jats:italic>I<\/jats:italic><jats:sub>h<\/jats:sub> activation curve and increased firing frequency, whereas DA caused a hyperpolarizing shift in the curve and decreased firing frequency.<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>Acute hypoxia and isohydric hypercapnia depolarized type I cells concomitant with increased excitation of adjacent PNs; the A2a receptor blocker SCH58261 inhibited both type I and PN responses during hypoxia, but only the PN response during isohydric hypercapnia.<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>We propose that adenosine and DA control firing frequency in chemosensory PNs via their opposing actions on <jats:italic>I<\/jats:italic><jats:sub>h<\/jats:sub>.<\/jats:p><\/jats:list-item>\n<\/jats:list><\/jats:p><\/jats:sec><jats:sec><jats:title>Abstract<\/jats:title><jats:p>Adenosine and dopamine (DA) act as neurotransmitters or neuromodulators at the carotid body (CB) chemosensory synapse, but their mechanisms of action are not fully understood. Using a functional co\u2010culture model of rat CB chemoreceptor (type I) cell clusters and juxtaposed afferent petrosal neurons (PNs), we tested the hypothesis that adenosine and DA act postsynaptically to modulate a hyperpolarization\u2010activated, cyclic nucleotide\u2010gated (HCN) cation current (<jats:italic>I<\/jats:italic><jats:sub>h<\/jats:sub>). In whole\u2010cell recordings from hypoxia\u2010responsive PNs, cAMP mimetics enhanced <jats:italic>I<\/jats:italic><jats:sub>h<\/jats:sub> whereas the HCN blocker ZD7288 (2\u00a0\u03bc<jats:sc>m<\/jats:sc>) reversibly inhibited <jats:italic>I<\/jats:italic><jats:sub>h<\/jats:sub>. Adenosine caused a potentiation of <jats:italic>I<\/jats:italic><jats:sub>h<\/jats:sub> (EC<jats:sub>50<\/jats:sub> \u223c 35\u00a0n<jats:sc>m<\/jats:sc>) that was sensitive to the A2a blocker SCH58261 (5\u00a0n<jats:sc>m<\/jats:sc>), and an \u223c16\u00a0mV depolarizing shift in <jats:italic>V<\/jats:italic><jats:sub>\u00bd<\/jats:sub> for voltage dependence of <jats:italic>I<\/jats:italic><jats:sub>h<\/jats:sub> activation. By contrast, DA (10\u00a0\u03bc<jats:sc>m<\/jats:sc>) caused an inhibition of <jats:italic>I<\/jats:italic><jats:sub>h<\/jats:sub> that was sensitive to the D2 blocker sulpiride (1\u201310\u00a0\u03bc<jats:sc>m<\/jats:sc>), and an \u223c11\u00a0mV hyperpolarizing shift in <jats:italic>V<\/jats:italic><jats:sub>\u00bd<\/jats:sub>. Sulpiride potentiated <jats:italic>I<\/jats:italic><jats:sub>h<\/jats:sub> in neurons adjacent to, but not distant from, type I cell clusters. DA also decreased PN action potential frequency whereas adenosine had the opposite effect. During simultaneous paired recordings, SCH58261 inhibited both the presynaptic hypoxia\u2010induced receptor potential in type I cells and the postsynaptic PN response. By contrast, SCH58261 inhibited only the postsynaptic PN response induced by isohydric hypercapnia. Confocal immunofluorescence confirmed the localization of HCN4 subunits in tyrosine hydroxylase\u2010positive chemoafferent neurons in tissue sections of rat petrosal ganglia. These data suggest that adenosine and DA, acting through A2a and D2 receptors respectively, regulate PN excitability via their opposing actions on <jats:italic>I<\/jats:italic><jats:sub>h<\/jats:sub>.<\/jats:p><\/jats:sec>","DOI":"10.1113\/jp274743","type":"journal-article","created":{"date-parts":[[2017,8,12]],"date-time":"2017-08-12T05:52:41Z","timestamp":1502517161000},"page":"3101-3117","source":"Crossref","is-referenced-by-count":33,"title":["Adenosine and dopamine oppositely modulate a hyperpolarization\u2010activated current <i>I<\/i><sub>h<\/sub> in chemosensory neurons of the rat carotid body in co\u2010culture"],"prefix":"10.1113","volume":"596","author":[{"given":"Min","family":"Zhang","sequence":"first","affiliation":[{"name":"Department of Biology McMaster University  1280 Main St. West Hamilton Ontario L8S 4K1 Canada"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Cathy","family":"Vollmer","sequence":"additional","affiliation":[{"name":"Department of Biology McMaster University  1280 Main St. West Hamilton Ontario L8S 4K1 Canada"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9514-858X","authenticated-orcid":false,"given":"Colin A.","family":"Nurse","sequence":"additional","affiliation":[{"name":"Department of Biology McMaster University  1280 Main St. West Hamilton Ontario L8S 4K1 Canada"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2017,9,21]]},"reference":[{"key":"e_1_2_7_2_1","first-page":"32","article-title":"From funny current to HCN channels: 20\u00a0years of excitation","volume":"17","author":"Accili EA","year":"2002","journal-title":"News Physiol 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