The mechanistic response of neurotransmitter systems to a variety of long term manipulations, for example in stress or illness, is a central issue in neurobiology. The plasticity of neurotransmitter biosynthesis is much more intricately regulated than previously appreciated. This proposal will study molecular aspects of the regulation of biosynthesis of norepinephrine, a transmitter that plays a crucial role in a surprisingly large number of functions in the CNS and periphery. Tyrosine hydroxylase (TH) and dopamine beta-hydroxylase (DBH), two of the enzymes involved in norepinephrine biosynthesis, are regulated in response to long term physiological, pharmacological and environmental stimuli. A molecular description of their regulated expression will be invaluable both as a model for neurotransmitter regulation in general as well as in the specific elucidation of the mechanisms which regulate the catecholaminergic neuronal system. This project will: I. Delineate the differences between membrane-bound and soluble forms of DBH. Determine what is the mode of membrane attachment of DBH and the nature of the post-translational processing from the membrane-bound to the soluble form. II. Determine the regulation of expression of DBH and TH in vivo in tissues which synthesize norepinephrine, specifically in the adrenal medulla and in the locus coeruleus (LC) of the central nervous system. III. Delineate the regulation of expression of DBH and TH in PC12 cells and primary chromaffin cells. Study the regulation of mRNA levels and transcription of the DBH gene in response to growth factors, cyclic AMP analogs and glucocorticoids and combinations of these treatments. IV. Define upstream regulatory elements in the rat DBH gene. I postulate that there are regulatory elements for cAMP, glucocorticoids and growth factors. Elements for tissue specific expression will be determined. The results of this study will provide a detailed mechanistic interpretation of the long term regulation of norepinephrine biosynthesis, which will have important implications for the responsiveness of the nervous system to prolonged stress and disease, such as hypertension, schizophrenia, depression and dementia of the Alzheimer's type.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS028869-09
Application #
6187254
Study Section
Special Emphasis Panel (ZRG1-NEUC (02))
Program Officer
Murphy, Diane
Project Start
1990-08-01
Project End
2001-03-31
Budget Start
2000-04-01
Budget End
2001-03-31
Support Year
9
Fiscal Year
2000
Total Cost
$229,637
Indirect Cost
Name
New York Medical College
Department
Biochemistry
Type
Schools of Medicine
DUNS #
City
Valhalla
State
NY
Country
United States
Zip Code
10595
Papanikolaou, Nikolaos A; Tillinger, Andrej; Liu, Xiaoping et al. (2014) A systems approach identifies co-signaling molecules of early growth response 1 transcription factor in immobilization stress. BMC Syst Biol 8:100
Serova, L I; Nostramo, R; Veerasirikul, M et al. (2011) Varied mechanisms of oestradiol-mediated regulation of dopamine ?-hydroxylase transcription. J Neuroendocrinol 23:168-76
Tillinger, Andrej; Sollas, Anne; Serova, Lidia I et al. (2010) Vesicular monoamine transporters (VMATs) in adrenal chromaffin cells: stress-triggered induction of VMAT2 and expression in epinephrine synthesizing cells. Cell Mol Neurobiol 30:1459-65
Sabban, Esther L; Maharjan, Shreekrishna; Nostramo, Regina et al. (2010) Divergent effects of estradiol on gene expression of catecholamine biosynthetic enzymes. Physiol Behav 99:163-8
Kvetnansky, Richard; Sabban, Esther L; Palkovits, Miklos (2009) Catecholaminergic systems in stress: structural and molecular genetic approaches. Physiol Rev 89:535-606
Liu, Xiaoping; Serova, Lidia; Kvetnansky, Richard et al. (2008) Identifying the stress transcriptome in the adrenal medulla following acute and repeated immobilization. Ann N Y Acad Sci 1148:1-28
Cheng, Shu-Yuan; Serova, Lidia I; Glazkova, Dina et al. (2008) Regulation of rat dopamine beta-hydroxylase gene transcription by early growth response gene 1 (Egr1). Brain Res 1193:1-11
Sabban, Esther L (2007) Catecholamines in stress: molecular mechanisms of gene expression. Endocr Regul 41:61-73
Gueorguiev, Volodia D; Cheng, Shu-Yuan; Sabban, Esther L (2006) Prolonged activation of cAMP-response element-binding protein and ATF-2 needed for nicotine-triggered elevation of tyrosine hydroxylase gene transcription in PC12 cells. J Biol Chem 281:10188-95
Sabban, Esther L; Liu, Xiaoping; Serova, Lidia et al. (2006) Stress triggered changes in gene expression in adrenal medulla: transcriptional responses to acute and chronic stress. Cell Mol Neurobiol 26:845-56

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