Corey Smith

Associate Professor

Ph.D., University of Colorado Health Sciences Center, 1996
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Cellular Mechanisms of the Sympatho-Adrenal Acute Stress Response

RESEARCH DESCRIPTION

Stress is a physiological response of the sympathetic nervous system to environmental pressures. If left unchecked it can lead to patho-physiologies such as hypertension and diabetes. Chromaffin cells of the adrenal medulla are a primary neuroendocrine output of the sympathetic nervous system and release transmitter molecules into the circulation. At basal sympathetic tone, catecholamine output regulates homeostatic processes including enteric function, vascular tone and insulin secretion. Stress-mediated sympathetic activation leads to elevated catecholamine secretion, increasing cardiac output and glucagon levels. Stress also evokes peptide transmitter release, including analgesic enkephalins, which allow the organism to focus on escape and defense.

We are investigating the mechanism by which chromaffin cells differentially release cargos in an activity-dependent manner. Catecholamines and neuropeptides are co-packaged in the same granule, thus it was assumed that both types of transmitter are released by a single exocytic mechanism. However, this is inconsistent with reports of activity-dependent differential release of catecholamine and neuropeptides from chromaffin cells. We employ varied electrophysiological and imaging techniques to show activity-dependent differences in the mode of granule fusion under physiological stimulation. Work to this point shows that basal firing preferentially evokes catecholamine release through a restricted granule fusion intermediate (an ?-figure). Higher activity levels that mimic acute-stress lead to a dilation of the fusion pore and releases both the catecholamine and neuropeptide cargos. These differences indicate that differential transmitter release from adrenal chromaffin cells may be achieved through a size-exclusion mechanism.

Upon sympathetic stimulation, chromaffin cells fire action potentials that open voltage-gated calcium channels and evoke the exocytic release of catecholamines. Thus control of the Ca2+ influx in chromaffin cells represents a target for the regulation of multiple physiological functions. We are investigating isoform-specific Ca2+ influx under basal and acute sympathetic stress conditions. We find a strict preference for activation of Ca2+ channel subtypes under sympathetic tone versus acute stress. This will aid in developing approaches to controlling serum catecholamine levels under specific metabolic states and will help develop more directed therapies to controlling blood pressure and/or insulin levels under rest or stress physiological states.

RELATED RESEARCH AREAS

View Corey Smith's Publications on PubMed