ACELL April 47/4

He, L., B. Dinger, and S. Fidone. Cellular mechanisms involved in carotid body inhibition produced by atrial natriuretic peptide. Am J Physiol Cell Physiol 278: C845–C852, 2000.—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 K1 and Ca21 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 K1 and Ca21 currents. We also investigated the effects of these specific inhibitors on intracellular Ca21 concentration and carotid sinus nerve (CSN) activity under normoxic and hypoxic conditions. Voltage-dependent K1 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 Ca21 currents induced by APIII. Furthermore, APIII depressed hypoxia-evoked elevations of intracellular Ca21, 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 K1 and Ca21 channel proteins in the chemosensory type I cells.