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Department of Physiology, University of Utah School of Medicine, Salt Lake City, Utah 84108
Atrial natriuretic peptide (ANP) and its analog, atriopeptin III (APIII), inhibit carotid body chemoreceptor nerve activity evoked by hypoxia. In the present study, we have examined the hypothesis that the inhibitory effects of ANP and APIII are mediated by cyclic GMP and protein kinase G (PKG) via the phosphorylation and/or dephosphorylation of K+ and Ca2+ channel proteins that are involved in regulating the response of carotid body chemosensory type I cells to low-O2 stimuli. In freshly dissociated rabbit type I cells, we examined the effects of a PKG inhibitor, KT-5823, and an inhibitor of protein phosphatase 2A (PP2A), okadaic acid (OA), on K+ and Ca2+ currents. We also investigated the effects of these specific inhibitors on intracellular Ca2+ concentration and carotid sinus nerve (CSN) activity under normoxic and hypoxic conditions. Voltage-dependent K+ currents were depressed by hypoxia, and this effect was significantly reduced by 100 nM APIII. The effect of APIII on this current was reversed in the presence of either 1 µM KT-5823 or 100 nM OA. Likewise, these drugs retarded the depression of voltage-gated Ca2+ currents induced by APIII. Furthermore, APIII depressed hypoxia-evoked elevations of intracellular Ca2+, an effect that was also reversed by OA and KT-5823. Finally, CSN activity evoked by hypoxia was decreased in the presence of 100 nM APIII, and was partially restored when APIII was presented along with 100 nM OA. These results suggest that ANP initiates a cascade of events involving PKG and PP2A, which culminates in the dephosphorylation of K+ and Ca2+ channel proteins in the chemosensory type I cells.
chemoreceptor inhibition; cell currents; protein kinase G; protein phosphatase 2A; atrial natriuretic peptide
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