NADPH Oxidase-Dependent Regulation of T-Type Ca<sup>2+</sup>Channels and Ryanodine Receptors Mediate the Augmented Exocytosis of Catecholamines from Intermittent Hypoxia-Treated Neonatal Rat Chromaffin Cells

Journal of Neuroscience - Tập 30 Số 32 - Trang 10763-10772 - 2010
Dangjai Souvannakitti1, Jayasri Nanduri2, Guoxiang Yuan2, Ganesh K. Kumar2, Aaron P. Fox3,4,5,6, Nanduri R. Prabhakar2
1The Center for Systems Biology of O2 Sensing, Department of Medicine, University of Chicago, Chicago, Illinois 60637, USA.
2The Center for Systems Biology of O
3Department of Medicine, The University of Chicago, MC 5068, 5841 S. Maryland Avenue, Chicago, IL 60637.
4Neurobiology, Pharmacology, and Physiology, University of Chicago, Chicago, Illinois 60637
5Sensing,
6Sensing, Departments of 1 Medicine and

Tóm tắt

Nearly 90% of premature infants experience the stress of intermittent hypoxia (IH) as a consequence of recurrent apneas (periodic cessation of breathing). In neonates, catecholamine secretion from the adrenal medulla is critical for maintaining homeostasis under hypoxic stress. We recently reported that IH treatment enhanced hypoxia-evoked catecholamine secretion and [Ca2+]iresponses in neonatal rat adrenal chromaffin cells and involves reactive oxygen species (ROS). The purpose of the present study was to identify the source(s) of ROS generation and examine the mechanisms underlying the enhanced catecholamine secretion by IH. Neonatal rats of either sex (postal day 0–5) were exposed to either IH or normoxia. IH treatment increased NADPH oxidase (NOX) activity, upregulated NOX2 and NOX4 transcription in adrenal medullae, and a NOX inhibitor prevented the effects of IH on hypoxia-evoked chromaffin cell secretion. IH upregulated Cav3.1 and Cav3.2 T-type Ca2+channel mRNAs via NOX/ROS signaling and augmented T-type Ca2+current in IH-treated chromaffin cells. Mibefradil, a blocker of T-type Ca2+channels attenuated the effects of hypoxia on [Ca2+]iand catecholamine secretion in IH-treated cells. In Ca2+-free medium, IH-treated cells exhibited higher basal [Ca2+]ilevels and more pronounced [Ca2+]iresponses to hypoxia compared with controls, and blockade of ryanodine receptors (RyRs) prevented these effects. RyR2 and RyR3 mRNAs were upregulated, RyR2 was S-glutathionylated in IH-treated adrenal medullae, and NOX/ROS inhibitors prevented these effects. These results demonstrate that neonatal IH treatment leads to NOX/ROS-dependent recruitment of T-type Ca2+channels and RyRs, resulting in augmented [Ca2+]imobilization and catecholamine secretion.

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Journal of Neuroscience

Tập 30 Số 32

10763-10772

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