Enhanced Neurotrophin Signaling Following Chronic Hypoxia Potentiates Catecholamine Release from Adrenal Chromaffin Cells
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abstract
Environmental stressors, including chronic hypoxia, stimulate catecholamine secretion from adrenomedullary chromaffin cells (AMCs); however, the underlying molecular mechanisms remain unclear. Here, we investigated the role of brain‐derived neurotrophic factor (BDNF) signaling in rat AMCs exposed to chronic hypoxia. In rat adrenal glands, BDNF and its tropomyosin‐related kinase B (TrkB) receptor were highly expressed in the cortex and medulla, respectively. Exposure of AMCs to chronic hypoxia (2% O2; 48 hr) in vitro caused a significant increase in TrkB mRNA expression. A similar increase was observed in an immortalized chromaffin cell line (MAH cells); however, it was absent in MAH cells deficient in the transcription factor HIF‐2a. Activation of TrkB with a specific agonist, 7,8 dihydroxyflavone (7,8 DHF), or BDNF on chronically hypoxic (Chox) AMCs increased intracellular Ca2+ ([Ca2+]i) and quantal catecholamine release to a greater extent than normoxic (Nox; 21% O2) controls. The TrkB‐induced [Ca2+]i rise was sensitive to the tyrosine kinase inhibitor K252a and nickel, but not the Ca2+ store‐depleting agent, cyclopiazonic acid. TrkB activation also induced membrane depolarization and action potential firing that occurred with a higher frequency in CHox cells. This was accompanied by a conductance increase, and the spike discharge was inhibited by pyrazole‐3, a selective TRPC3 channel blocker. These data demonstrate that, during chronic hypoxia, enhancement of BDNF‐TrkB signaling increases membrane excitability and extracellular Ca2+ influx in chromaffin cells, which leads to a marked potentiation in catecholamine secretion. This work was funded by the Natural Sciences and Engineering Research Council. A.S. is a NSERC Post‐doctoral Fellow.
