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 endocrine output of the sympathetic nervous system and secrete a host of transmitter molecules, including catecholamines and peptide transmitters, through the fusion of dense core secretory granules. At basal firing rates, set by the sympathetic tone, catecholamine output regulates homeostatic processes such as 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 enkephalin which acts as an analgesic and allows the organism to focus on escape and defense. Our goal is to understand how chromaffin cells regulate the release of catecholamine and signaling peptides under physiological basal-firing and stress activation. Cellular mechanisms for catecholamine release have been studied, but peptide transmitter release is less well understood under these conditions. In this proposal we will test that, under basal firing, chromaffin granules undergo a restricted fusion with the cell surface and selectively release catecholamine. We will test that stress-activation induces a full fusion and collapse of the granule leading to release of both catecholamine and peptide cargos. We will employ electrophysiological, electrochemical, fluorescence imaging, immunocytochemical and biochemical approaches. We will test for exocytosis of catecholamine and protein cargo from chromaffin granules under basal-firing and stress-activated states. We will test the roles of key molecules in the exo-endocytic mechanism and we will measure the degree granule collapse into the cell surface during the exo-endocytic cycle. This data will provide a fundamental understanding of the cellular and molecular mechanisms for the endocrine stress response in chromaffin cells.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
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Biophysics of Synapses, Channels, and Transporters Study Section (BSCT)
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Mitler, Merrill
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Case Western Reserve University
Schools of Medicine
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Smith, Corey B; Eiden, Lee E (2012) Is PACAP the major neurotransmitter for stress transduction at the adrenomedullary synapse? J Mol Neurosci 48:403-12
Chan, Shyue-An; Hill, Jacqueline; Smith, Corey (2012) Reduced calcium current density in female versus male mouse adrenal chromaffin cells in situ. Cell Calcium 52:313-20
Chan, Shyue-An; Doreian, Bryan; Smith, Corey (2010) Dynamin and myosin regulate differential exocytosis from mouse adrenal chromaffin cells. Cell Mol Neurobiol 30:1351-7
Kuri, Barbara A; Chan, Shyue-An; Smith, Corey B (2009) PACAP regulates immediate catecholamine release from adrenal chromaffin cells in an activity-dependent manner through a protein kinase C-dependent pathway. J Neurochem 110:1214-25
Doreian, Bryan W; Fulop, Tiberiu G; Meklemburg, Robert L et al. (2009) Cortical F-actin, the exocytic mode, and neuropeptide release in mouse chromaffin cells is regulated by myristoylated alanine-rich C-kinase substrate and myosin II. Mol Biol Cell 20:3142-54
Doreian, Bryan W; Fulop, Tiberiu G; Smith, Corey B (2008) Myosin II activation and actin reorganization regulate the mode of quantal exocytosis in mouse adrenal chromaffin cells. J Neurosci 28:4470-8
Fulop, Tiberiu; Doreian, Bryan; Smith, Corey (2008) Dynamin I plays dual roles in the activity-dependent shift in exocytic mode in mouse adrenal chromaffin cells. Arch Biochem Biophys 477:146-54
Fulop, Tiberiu; Smith, Corey (2007) Matching native electrical stimulation by graded chemical stimulation in isolated mouse adrenal chromaffin cells. J Neurosci Methods 166:195-202
Kuri, Barbara A; Khan, Shakil A; Chan, Shyue-An et al. (2007) Increased secretory capacity of mouse adrenal chromaffin cells by chronic intermittent hypoxia: involvement of protein kinase C. J Physiol 584:313-9
Polo-Parada, L; Chan, S-A; Smith, C (2006) An activity-dependent increased role for L-type calcium channels in exocytosis is regulated by adrenergic signaling in chromaffin cells. Neuroscience 143:445-59

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