Circadian rhythms and environmental lighting regulate nightly synthesis of melatonin, the pineal hormone implicated in various aspects of human physiology including sleep-wakefulness cycle and manic-depressive illnesses. To understand the cellular mechanisms underlying the dynamic regulation of melatonin production, a substractive hybridization technique was employed to search for messages differentially expressed during day and night in the rat pineal gland. Using this technique, an alternatively spliced form of the Wilson's disease gene (PIneal Night-specific ATPase = PINA) was found to be prominently expressed in night pineal gland. Tissue distribution and temporal expression pattern of PINA are identical to that of serotonin N-acetyltransferase (NAT), the rate limiting enzyme in melatonin synthesis, suggesting a role of PINA in melatonin production. Long Evans Cinnamon (LEC) rats are animal models of the Wilson's disease in which PINA is mutated. Preliminary studies revealed that the activity of serotonin NAT is decreased in these rats while that of hydroxyindole-O-methyltransferase (HIOMT), the second and the last enzyme in melatonin synthesis, is unaltered. This proposal is designed to further analyze the functional consequence of PINA mutation in LEC pineal and to elucidate molecular mechanism underlying this defect.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Small Research Grants (R03)
Project #
7R03MH057299-03
Application #
6051768
Study Section
Molecular, Cellular, and Developmental Neurobiology Review Committee (MCDN)
Project Start
1997-07-01
Project End
1999-06-30
Budget Start
1998-07-02
Budget End
1999-06-30
Support Year
3
Fiscal Year
1998
Total Cost
Indirect Cost
Name
Carnegie Institution of Washington, D.C.
Department
Type
DUNS #
072641707
City
Washington
State
DC
Country
United States
Zip Code
20005
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Borjigin, J; Deng, J; Wang, M M et al. (1999) Circadian rhythm of patched1 transcription in the pineal regulated by adrenergic stimulation and cAMP. J Biol Chem 274:35012-5
Li, X; Borjigin, J; Snyder, S H (1998) Molecular rhythms in the pineal gland. Curr Opin Neurobiol 8:648-51
Li, X; Chen, S; Wang, Q et al. (1998) A pineal regulatory element (PIRE) mediates transactivation by the pineal/retina-specific transcription factor CRX. Proc Natl Acad Sci U S A 95:1876-81