Regulation of the sympatho-adrenal stress response.
Varied sympathetic activity is translated into differential hormonal profiles under the sympatho-adrenal stress response. Our lab studies multiple components of this vital physiological response system. We study the synaptic peptide transmitter regulation of hormone release at the splanchnic-adrenal synapse and we study the regulation of activity-dependent differential transmitter release from neuroendocrine adrenal medullary chromaffin cells.
Activity-dependent differential transmitter release.
A cartoon representation of the shift in the secretory mode from neuroendocrine adrenal chromaffin cells. At basal stimulation, as under sympathetic tone, a sub-fraction of soluble catecholamine is released through a restricted fusion pore. This mode of exocytosis is termed "kiss and run", referring to the omega-like profile of the fused granule. Under elevated stimulation, as under the sympatho-adrenal stress reflex, the fusion pore is driven to expand, collapsing the granule into the cell surface. This "full collapse" mode of secretion facilitates maximal release of catecholamine as well as the proteinaceous peptide transmitter-containing granule core.
Activity-dependent release of adrenal peptide stress hormones.
Environmental threat, physical exertion or injury and psychological strain all lead to the initiation of the sympatho-adrenal “fight or flight” stress response. Neuroendocrine adrenal medullary chromaffin cells receive excitatory synaptic input from the sympathetic splanchnic nerve. Splanchnic activation causes adrenal chromaffin cells to release catecholamines as well as a diverse array of neuro- and vaso-active peptide transmitters into the circulation. Different levels of stress result in the differential release of catecholamine versus peptide transmitters to formulate the appropriate physiological response. All secreted hormones, catecholamines as well as multiple species of peptide transmitters, are co-packaged in the same secretory granules. Thus, differential hormone release is regulated at a step after granule fusion. Under basal chromaffin cell excitation, set by the sympathetic tone, selective release of freely-soluble catecholamine occurs through a transient fusion event, characterized by a narrow, structured exocytic fusion pore between the granule lumen and the extracellular space. Under sympathetic tone, selective and modest catecholamine release plays an important role in the “rest and digest” metabolic status of energy storage, regulating homeostatic physiological functions including pancreatic insulin secretion, increased blood flow to the viscera and maintenance of basal cardiac activity. In response to stress, increased chromaffin cell stimulation modulates the mode of secretory granule fusion, leading to the expansion of the exocytic fusion pore to maximize catecholamine release and facilitate exocytosis of the co-packaged adrenal peptide transmitters. Elevated serum catecholamine levels, in combination with adrenal-derived peptide transmitters, are core effectors of the sympathetic “fight or flight” stress response. Together they regulate multiple processes that prepare for defense or escape, including generalized analgesia (enkephalin), increased cardiac output (elevated catecholamines), blood flow to skeletal muscle (atrial natriuretic factor, Neuropeptide Y) and blood glucose (pancreastatin). Thus, regulated expansion of the secretory fusion pore represents a key element of the acute stress response.
PACAP as a primary effector of the sympatho-adrenal stress response.
Environmental insult, injury, illness and psychological trauma all evoke the “fight or flight” sympathetic stress response. Specific stressors selectively evoke elevations in serum epinephrine (Epi) or norepinephrine (NE) to formulate the appropriate physiological response. For example, hypoglycemia leads to selective Epi release to increase hepatic blood flow, increase glucagon secretion and to decrease insulin sensitivity, all in order to elevate blood glucose levels. Acute cold stress results in selective NE release to constrict peripheral vasculature in order to preserve body heat. Hypoxia results in an equivalent increase in both Epi and NE to increase cardiac output and pulmonary function to deliver oxygen to the tissues of the body. Norepinephrine is released from sympathetic nerve terminals throughout the periphery, as well as from neuroendocrine chromaffin cells of the adrenal medulla while the adrenal medullary chromaffin cells are the sole source for serum Epi. There are two secretory isotypes of adrenal chromaffin cell; Epi-secreting or NE-secreting. Thus, differential NE versus Epi release dictates a stressor-specific activation of the adrenal medullary Epi-secreting chromaffin cells. Adrenal chromaffin cells receive synaptic input from the sympathetic splanchnic nerve. Previous studies have shown that the splanchnic synapse utilizes a dual transmitter excitation system. Under basal sympathetic tone, the splanchnic terminals release rapidly acting and deactivating acetylcholine to fine-tune adrenal excitation. Under this “rest and digest” condition, the sympathetic nervous systems works in concert with the parasympathetic nervous system to regulate homeostatic processes. Stress evokes increased sympathetic drive and signals persistent and robust adrenal excitation through splanchnic release of the potent chromaffin cell secretagogue, Pituitary Adenylate Cyclase Activating Peptide (PACAP). Thus, splanchnic PACAP is the stress transducer in the sympatho-adrenal stress reflex. Despite its physiological importance, relatively little is known of how splanchnic PACAP controls differential Epi versus NE release from the adrenal medulla.
- Tiberiu Fulop, Stephen Radabaugh and Corey Smith (2005) Activity-dependent differential transmitter release in mouse adrenal chromaffin cells. Journal of Neuroscience 2005 25: 7324-7332.
- Tiberiu Fulop and Corey Smith (2006) Physiological Stimulation Regulates Fusion Pore Dilation Through Calcium activation of Protein Kinase C in Mouse Chromaffin Cells. Biochemical Journal 399(1):111-9
- Barbara A. Kuri, Shakil A. Khan, Shyue-An Chan, Nanduri R. Prabhakar, and Corey Smith (2007) Increased Secretory Capacity of Mouse Adrenal Chromaffin Cells By Intermittent Hypoxia: Involvement of Protein Kinase C. Journal of Physiology (London) 584: 313-319.
- Jackie Hill, Seong-Ki Lee, Prattana Samasilp and Corey Smith (2012) Pituitary Adenylate Cyclase-Activating Peptide (PACAP) enhances electrical coupling in the mouse adrenal medulla. American Journal of Physiology – Cell Physiology. 303(3):C257-66.
- Prattana Samasilp, Shyue-An Chan, Corey Smith (2012) Activity-dependent fusion pore expansion regulated by a calcineurin0dependent dynamin-syndapin pathway in mouse adrenal chromaffin cells. The Journal of Neuroscience. 32(30):10438-47.