Catecholamine neurotransmitters, dopamine, norepinephrine and epinephrine (adrenalin) are involved in a broad range of regulatory and CNS functions, as well as, Alzheimer’s disease, schizophrenia, manic depressive illnesses, and Parkinson’s disease). Research in the Waymire laboratory examines the regulation of catecholamines at the cellular and biochemical level, focusing on the mechanisms responsible for changes in synthesis regulation that occur in normal function and disease.
|Schematic representing the phosphorylation of tyrosine hydroxylase (TOHase) by four protein kinase systems.|
Catecholamine neurotransmitter synthesis is regulated both rapidly and on a long-term basis in response to increased neural activity. Short-term regulation occurs by increasing the activity of tyrosine hydroxylase, the controlling enzyme in catecholamine biosynthesis. This is accomplished by phosphorylation of tyrosine hydroxylase to increase its function. A regulatory protein, 14-3-3, is necessary for Ca2+-mediated tyrosine hydroxylase regulation. The Waymire laboratory is working to resolve the relative role of phosphorylation versus 14-3-3 in short-term catecholamine synthesis regulation.
The long-term regulation of neurotransmitter synthesis occurs by increasing tyrosine hydroxylase mRNA and protein present in the nerve cells. This occurs in two ways. In one, the amount of tyrosine hydroxylase mRNA increases through an increase in the mRNA synthesis in response to increased neural stimulation. In the second, a decrease the degradation rate of tyrosine hydroxylase mRNA occurs in response to neural stimulation. The latter mechanism is poorly understood and a current focus of the Waymire lab studies.
To address the understanding of catecholamine synthesis regulation the Waymire laboratory uses isolated catecholamine cells derived from the adrenal medulla of cattle. These neurosecretory cells, which make and secrete catecholamines, provide a means to understand the essential regulatory mechanisms that function in catecholamine cells in general.
Salvatore, MF, Waymire, JC, Haycock. (2001) Depolarization-stimulated catecholamine biosynthesis: involvement of protein kinases and tyrosine hydroxylase phosphorylation sites. J. Neurochem. 79:1-13.
Perez, RG, Waymire, JC, Slagel, SL, Glessner, AA, Liu, JJ, Zigmond, MJ. (2002) A role for alpha synuclein in the regulation of dopamine biosynthesis. J. Neuroscience 22, 3090-3099.
Waymire, JC, Haycock, JW. (2002) Lack of regulation of aromatic L-amino acid decarboxylase in intact bovine chromaffin cells. J. Neurochem. 81: 589-593.
Waymire, JC. (2002) Activity-dependent regulation of neurotransmitter synthesis. Encyclopedia of Learning and Memory, Byrne, JW (Ed.), Macmillan, New York, pp 1-5.
Roe, D, Craviso, GL, Waymire, JC. (2004) Nicotinic stimulation modulates tyrosine hydroxylase mRNA half-life and protein binding to the 3’UTR in a manner that requires transcription, Mol. Brain Research 120: 91-102.
Kobori N, Waymire JC, Haycock JW, Clifton GL, Dash PK. (2004) Enhancement of tyrosine hydroxylase phosphorylation and activity by glial cell line-derived neurotrophic factor. J. Biol. Chem. 279: 2182-2191.
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