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EPAC signalling pathways are involved in low P O2 chemoreception in carotid body chemoreceptor cells
Author(s) -
Rocher Asuncion,
Caceres Ana I.,
Almaraz Laura,
Gonzalez Constancio
Publication year - 2009
Publication title -
the journal of physiology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.802
H-Index - 240
eISSN - 1469-7793
pISSN - 0022-3751
DOI - 10.1113/jphysiol.2009.172072
Subject(s) - carotid body , chemoreceptor , endocrinology , medicine , hypoxia (environmental) , chemistry , hypercapnia , biology , acidosis , stimulation , receptor , organic chemistry , oxygen
Chemoreceptor 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 (≈ 46 mmHg) produces smaller depolarisations and comparable Ca 2+ transients but a much higher catecholamine (CA) release response in intact CBs than intense acidic/hypercapnic stimuli (20% CO 2 , pH 6.6). Similarly, intense hypoxia (≈ 20 mmHg) produces smaller depolarizations and Ca 2+ transients in isolated chemoreceptor cells but a higher CA release response in intact CBs than a pure depolarizing stimulus (30–35 m m external K + ). Studying the mechanisms responsible for these differences we have found the following. (1) Acidic hypercapnia inhibited I Ca (∼60%; whole cell) and CA release (∼45%; intact CB) elicited by ionomycin and high K + . (2) Adenylate cyclase inhibition (SQ‐22536; 80 μ m ) 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 × IC 50 ) did not alter the hypoxic release response. (4) The Epac (exchange protein activated by cAMP) activator (8‐pCPT‐2′‐ O ‐Me‐cAMP, 100 μ m ) reversed the effects of the cyclase inhibitor. (5) The Epac inhibitor brefeldin A (100 μ m ) inhibited (54%) hypoxic induced release. Our findings show for the first time that an Epac‐mediated pathway mediates O 2 sensing/transduction in chemoreceptor cells.