{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,1,9]],"date-time":"2026-01-09T18:22:44Z","timestamp":1767982964637,"version":"3.49.0"},"reference-count":68,"publisher":"American Physiological Society","issue":"12","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["American Journal of Physiology-Regulatory, Integrative and Comparative Physiology"],"published-print":{"date-parts":[[2013,6,15]]},"abstract":"<jats:p>Consistent with a critical role in respiratory and autonomic stress responses, the carotid bodies are strongly excited by pituitary adenylate cyclase-activating polypeptide (PACAP), a neuropeptide implicated in stress responses throughout the sympathetic nervous system. PACAP excites isolated carotid body glomus cells via activation of PAC1 receptors, with one study suggesting PAC1-induced excitation is due entirely to protein kinase A (PKA)-mediated inhibition of TASK channels. However, in other systems, PAC1 is known to be coupled to multiple intracellular signaling pathways, including PKA, phospholipase C (PLC), phospholipase D (PLD), and protein kinase C (PKC), that trigger multiple downstream effectors including increased Ca<jats:sup>2+<\/jats:sup>mobilization, inhibition of various K<jats:sup>+<\/jats:sup>channels, and activation of nonselective cation channels. This study tests if non-PKA\/TASK channel signaling helps mediate the stimulatory effects of PACAP on the carotid body. Using an ex vivo arterially perfused rat carotid body preparation, we show that PACAP-38 stimulates carotid sinus nerve activity in a biphasic manner (peak response, falling to plateau). PKA blocker H-89 only reduced the plateau response (\u223c41%), whereas the TASK-1-like K<jats:sup>+<\/jats:sup>channel blocker\/transient receptor potential vanilloid 1 channel agonist anandamide only inhibited the peak response (\u223c48%), suggesting involvement of additional pathways. The PLD blocker CAY10594 significantly inhibited both peak and plateau responses. The PLC blocker U73122 decimated both peak and plateau responses. Brefeldin A, a blocker of Epac (cAMP-activated guanine exchange factor, reported to link G<jats:sub>s<\/jats:sub>-coupled receptors with PLC\/PLD), also reduced both phases of the response, as did blocking signaling downstream of PLC\/PLD with the PKC inhibitors chelerythrine chloride and GF109203X. Suggesting the involvement of non-TASK ion channels in the effects of PACAP, the A-type K<jats:sup>+<\/jats:sup>channel blocker 4-aminopyridine, and the putative transient receptor potential channel (TRPC)\/T-type calcium channel blocker SKF96365 each significantly inhibited the peak and steady-state responses. These data suggest the stimulatory effect of PACAP-38 on carotid body sensory activity is mediated through multiple signaling pathways: the PLC-PKC pathways predominates, with TRPC and\/or T-type channel activation and K<jats:sub>v<\/jats:sub>channel inactivation; only partial involvement is attributable to PKA and PLD activation.<\/jats:p>","DOI":"10.1152\/ajpregu.00465.2012","type":"journal-article","created":{"date-parts":[[2013,4,18]],"date-time":"2013-04-18T02:51:47Z","timestamp":1366253507000},"page":"R1070-R1084","source":"Crossref","is-referenced-by-count":17,"title":["Stress peptide PACAP engages multiple signaling pathways within the carotid body to initiate excitatory responses in respiratory and sympathetic chemosensory afferents"],"prefix":"10.1152","volume":"304","author":[{"given":"Arijit","family":"Roy","sequence":"first","affiliation":[{"name":"Department of Physiology and Pharmacology, Hotchkiss Brain Institute, Faculty of Medicine, University of Calgary, Calgary, Alberta, Canada"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Fatemeh","family":"Derakhshan","sequence":"additional","affiliation":[{"name":"Department of Physiology and Pharmacology, Hotchkiss Brain Institute, Faculty of Medicine, University of Calgary, Calgary, Alberta, Canada"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Richard J. 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