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Title

EPAC signalling pathways are involved in low PO2 chemoreception in carotid body chemoreceptor cells

AuthorsRocher, Asunción CSIC ORCID; Cáceres, Ana Isabel; Almaraz, Laura; González, Constancio CSIC
Issue Date2009
PublisherWiley-Blackwell
CitationJournal of Physiology 587(16): 4015-4027 (2009)
AbstractChemoreceptor cells of the carotid bodies (CB) are activated by hypoxia and acidosis, responding with an increase in their rate of neurotransmitter release, which in turn increases the electrical activity in the carotid sinus nerve and evokes a homeostatic hyperventilation. Studies in isolated chemoreceptor cells have shown that moderate hypoxias (PO2 ≈ 46 mmHg) produces smaller depolarisations and comparable Ca2+ transients but a much higher catecholamine (CA) release response in intact CBs than intense acidic/hypercapnic stimuli (20% CO2, pH 6.6). Similarly, intense hypoxia (PO2 ≈ 20 mmHg) produces smaller depolarizations and Ca2+ transients in isolated chemoreceptor cells but a higher CA release response in intact CBs than a pure depolarizing stimulus (30-35 mM external K+). Studying the mechanisms responsible for these differences we have found the following. (1) Acidic hypercapnia inhibited ICa (∼60%; whole cell) and CA release (∼45%; intact CB) elicited by ionomycin and high K+. (2) Adenylate cyclase inhibition (SQ-22536; 80 μM) inhibited the hypoxic release response (>50%) and did not affect acidic/hypercapnic release, evidencing that the high gain of hypoxia to elicit neurotransmitter release is cAMP dependent. (3) The last effect was independent of PKA activation, as three kinase inhibitors (H-89, KT 5720 and Rp-cAMP; ≥ 10 × IC50) did not alter the hypoxic release response. (4) The Epac (exchange protein activated by cAMP) activator (8-pCPT-2′-O-Me-cAMP, 100 μM) reversed the effects of the cyclase inhibitor. (5) The Epac inhibitor brefeldin A (100 μM) inhibited (54%) hypoxic induced release. Our findings show for the first time that an Epac-mediated pathway mediates O2 sensing/transduction in chemoreceptor cells. © 2009 The Authors. Journal compilation © 2009 The Physiological Society.
Publisher version (URL)http://dx.doi.org/10.1113/jphysiol.2009.172072
URIhttp://hdl.handle.net/10261/71654
DOIhttp://dx.doi.org/10.1113/jphysiol.2009.172072
Identifiersdoi: 10.1113/jphysiol.2009.172072
issn: 0022-3751
e-issn: 1469-7793
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