alexa NADPH oxidase-dependent regulation of T-type Ca2+ channels and ryanodine receptors mediate the augmented exocytosis of catecholamines from intermittent hypoxia-treated neonatal rat chromaffin cells.
Diabetes & Endocrinology

Diabetes & Endocrinology

Journal of Diabetes & Metabolism

Author(s): Souvannakitti D, Nanduri J, Yuan G, Kumar GK, Fox AP,

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Abstract 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+]i responses 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+]i and catecholamine secretion in IH-treated cells. In Ca2+-free medium, IH-treated cells exhibited higher basal [Ca2+]i levels and more pronounced [Ca2+]i responses 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+]i mobilization and catecholamine secretion. This article was published in J Neurosci and referenced in Journal of Diabetes & Metabolism

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