Journal
JOURNAL OF PHYSIOLOGY-LONDON
Volume 587, Issue 16, Pages 4015-4027Publisher
WILEY
DOI: 10.1113/jphysiol.2009.172072
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Funding
- DGICYT [BFU2007-61848]
- CIBER [CB06/06/0050]
- JCyL [GR242, VA104A08, SAN673-VA12/08]
- ISCiii [IP052561]
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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 (P-O2 approximate to 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 (P-O2 approximate to 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 I-Ca (similar to 60%; whole cell) and CA release (similar to 45%; intact CB) elicited by ionomycin and high K+. (2) Adenylate cyclase inhibition (SQ-22536; 80 mu 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 x IC50) did not alter the hypoxic release response. (4) The Epac (exchange protein activated by cAMP) activator (8-pCPT-2'-O-Me-cAMP, 100 mu m) reversed the effects of the cyclase inhibitor. (5) The Epac inhibitor brefeldin A (100 mu 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.
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