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Sci. Signal., 9 June 2009
Vol. 2, Issue 74, p. ec188
[DOI: 10.1126/scisignal.274ec188]

EDITORS' CHOICE

Hypoxia Catching Your Breath

Elizabeth M. Adler

Science Signaling, AAAS, Washington, DC 20005, USA

Catecholamine secretion from neonatal adrenomedullary chromaffin cells (AMCs) in response to episodes of asphyxia during birth leads to physiological changes that facilitate air breathing. The ability of AMCs to respond to hypoxia disappears postnatally concurrently with maturation of cholinergic innervation, and prenatal nicotine exposure is associated with decreased hypoxia-induced catecholamine secretion and increased risk of sudden infant death syndrome (SIDS). Buttigieg et al., who previously showed that chronic nicotine exposure interferes with the response of neonatal rat AMCs to hypoxia, explored the underlying mechanism. Hypoxia leads to inhibition of large-conductance and small-conductance Ca2+-activated K+ channels and of delayed rectifier K+ channels in AMCs; however, pharmacological analysis indicated that prenatal nicotine exposure did not affect K+ currents mediated by these channels, and immunocytochemical analysis confirmed their presence in AMCs from the nicotine-exposed pups. Prenatal nicotine exposure was, however, associated with an increase in the AMC current mediated by KATP channels, which are activated in hypoxia, and Western analysis confirmed the increased abundance of KATP Kir6.2 subunits. Hypoxia-mediated catecholamine secretion from AMCs depends on depolarization-dependent Ca2+ influx; increased activation of KATP channels should oppose this depolarization and, indeed, pharmacological analysis combined with spectrofluorimetric measurements of a Ca2+ indicator showed that the increase in KATP channels in AMCs from nicotine-exposed pups led to a decrease in the hypoxia-evoked Ca2+ signal. Like prenatal exposure, 7 days exposure of cultured AMCs to nicotine decreased the response to hypoxia; pharmacological analysis indicated that this depended on the {alpha}7 nicotinic acetylcholine receptor ({alpha}7 nAChR) and activation of protein kinase C (PKC) and Ca2+/calmodulin-dependent protein kinase (CaMK). Experiments in an immortalized chromaffin cell line confirmed that the nicotine-dependent increase in Kir6.2 abundance involved {alpha}7 nAChR, PKC, and CaMK and implicated HIF-2{alpha} (hypoxia-inducible factor-2{alpha}) in the response. Intriguingly, administration of a KATP channel inhibitor decreased the hypoxia-induced mortality of pups that had been prenatally exposed to nicotine. The authors thus propose that KATP channel inhibitors might have the potential to reduce mortality in newborns at risk of SIDS because of maternal smoking during pregnancy.

J. Buttigieg, S. Brown, A. C. Holloway, C. A. Nurse, Chronic nicotine blunts hypoxic sensitivity in perinatal rat adrenal chromaffin cells via upregulation of KATP channels: Role of {alpha}7 nicotinic acetylcholine receptor and hypoxia-inducible factor-2{alpha}. J. Neurosci. 29, 7137–7147 (2009). [Abstract] [Full Text]

Citation: E. M. Adler, Catching Your Breath. Sci. Signal. 2, ec188 (2009).


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