The inner region of the mammalian adrenal gland is composed of sympathetic neurons that release the catecholamine hormones, epinephrine and norepinephrine, into the blood. During the fight-or-flight response, these hormones are released from the adrenal gland and prime the organism for the sudden demands that may be placed upon the circulatory, respiratory, musculoskeletal and metabolic control systems. Consistent with their wide-reaching actions, the inappropriate activity of the adrenal gland has been associated with a variety of diseases including hypertension. The long-term objective of the proposed study is to determine the mechanisms that normally control the release of these adrenal hormones. One control pathway is believed to involve the secretion of transmitters that are co-released with the catecholamines and that mediate """"""""short feedback loops"""""""" within the gland itself. The identity of these co-transmitters and the condition(s) under which they released are not clear. However one strong candidate is neuropeptide Y, a polypeptide that is synthesized by chromaffin cells. Our hypothesis is that neuropeptide Y is an adrenal neurotransmitter whose release mediates short feedback loops that regulate catecholamine secretion. To test this hypothesis we have 3 specific aims that we will address using murine sympathetic neurons (chromaffin cells) and adrenal slices. In the first set of experiments we will test the hypothesis that the net effect of NPY is to increase the secretion of the catecholamines. Our second specific aim is to test the hypothesis that the release of NPY can regulate catecholamine secretion in an autocrine (cell-limited) manner. In the third set of experiments we will test the hypothesis that NPY can also regulate catecholamine secretion by altering the strength of the pre-synaptic input that normally limits catecholamine secretion. By using in vitro and in situ preparations and by employing electrophysiological and molecular techniques we will comprehensively determine whether local feedback pathways control catecholamine secretion. Although this work examines the regulation of the adrenal gland, similar mechanisms are likely to control the release of hormones from many different types of endocrine tissue.

Public Health Relevance

The inner region of the adrenal gland secretes hormones that regulate blood pressure and the cardiovascular system. Understanding how the release of these molecules is controlled is needed for the development of treatments that could correct their inappropriate or excessive release.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK080441-05
Application #
8247142
Study Section
Molecular Neuropharmacology and Signaling Study Section (MNPS)
Program Officer
Malozowski, Saul N
Project Start
2009-04-06
Project End
2014-03-31
Budget Start
2012-04-01
Budget End
2014-03-31
Support Year
5
Fiscal Year
2012
Total Cost
$208,761
Indirect Cost
$61,746
Name
Louisiana State Univ Hsc New Orleans
Department
Anatomy/Cell Biology
Type
Schools of Medicine
DUNS #
782627814
City
New Orleans
State
LA
Country
United States
Zip Code
70112
Gupta, Rajesh; Ma, Yunbing; Wang, Manqi et al. (2017) AgRP-Expressing Adrenal Chromaffin Cells Are Involved in the Sympathetic Response to Fasting. Endocrinology 158:2572-2584
Wang, Manqi; Wang, Qian; Whim, Matthew D (2016) Fasting induces a form of autonomic synaptic plasticity that prevents hypoglycemia. Proc Natl Acad Sci U S A 113:E3029-38
Wang, Qian; Wang, Manqi; Whim, Matthew D (2013) Neuropeptide y gates a stress-induced, long-lasting plasticity in the sympathetic nervous system. J Neurosci 33:12705-17
Wang, Qian; Whim, Matthew D (2013) Stress-induced changes in adrenal neuropeptide Y expression are regulated by a negative feedback loop. J Neurochem 125:16-25
Dubois, C J; Ramamoorthy, P; Whim, M D et al. (2012) Activation of NPY type 5 receptors induces a long-lasting increase in spontaneous GABA release from cerebellar inhibitory interneurons. J Neurophysiol 107:1655-65
Whim, Matthew D (2011) Pancreatic beta cells synthesize neuropeptide Y and can rapidly release peptide co-transmitters. PLoS One 6:e19478
Ramamoorthy, Prabhu; Wang, Qian; Whim, Matthew D (2011) Cell type-dependent trafficking of neuropeptide Y-containing dense core granules in CNS neurons. J Neurosci 31:14783-8