During his FIRST award, Dr. Piletz (the P.I.) and colleagues obtained evidence that non-adrenergic, imidazoline-selective receptors may be linked to depression. They found that unipolar depressed patients displayed a significant elevation (p=.002) in the binding density (Bmax) of p-125 IC) to an imidazoline-selective site on platelets, compared to healthy controls or patients with generalized anxiety disorder. The site on platelet plasma membranes was nearly identical to the Imidazoline-1 Receptor (I1R) in brain stem based on its affinity for a variety of compounds. Platelet p125 IC binding declined in patients following antidepressant drug treatment. Additionally, the binding of an analogue, p-NH4-3H-clonidine, was significantly elevated in the late luteal phase of women with dysphoric premenstrual changes (PMS), but not in women with normal menstrual cycles. In this application Dr. Piletz teams up with the discoverer of the I1R (Dr. Ernsberger) to investigate the molecular basis of regulation of I1 binding sites. A human megakaryocytic tumor cell line (MEG-01) will be used as a model of platelet receptors. This unique cell line was shown by Dr. Piletz to possess I1 sites, and can actually produce platelet-like particles in culture. Drawing on Dr. Piletz's postdoctoral experience with cDNA, and on a team of colleagues who have cloned similar receptors, this application proposes to clone the I1 receptor cDNA in MEG-01 cells. These studies will answer fundamental questions about the platelet I1 site, its regulation in health and disease and its possible utility as a marker in depressive illness and PMS.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Project (R01)
Project #
1R01MH049248-01
Application #
3388700
Study Section
Psychopathology and Clinical Biology Research Review Committee (PCB)
Project Start
1992-05-01
Project End
1995-04-30
Budget Start
1992-05-01
Budget End
1993-04-30
Support Year
1
Fiscal Year
1992
Total Cost
Indirect Cost
Name
Case Western Reserve University
Department
Type
Schools of Medicine
DUNS #
077758407
City
Cleveland
State
OH
Country
United States
Zip Code
44106
Chan, C K S; Burke, S L; Zhu, H et al. (2005) Imidazoline receptors associated with noradrenergic terminals in the rostral ventrolateral medulla mediate the hypotensive responses of moxonidine but not clonidine. Neuroscience 132:991-1007
Dontenwill, Monique; Piletz, John E; Chen, Michael et al. (2003) IRAS is an anti-apoptotic protein. Ann N Y Acad Sci 1009:400-12
Piletz, J E; Wang, G; Zhu, H (2003) Cell signaling by imidazoline-1 receptor candidate, IRAS, and the nischarin homologue. Ann N Y Acad Sci 1009:392-9
Zhu, He; Hayes, Jonathan; Chen, Michael et al. (2003) Relationship between platelet imidazoline receptor-binding peptides and candidate imidazoline-1 receptor, IRAS. Ann N Y Acad Sci 1009:439-46
Zhu, He; Paul, Ian A; Stec, David E et al. (2003) Non-adrenergic exploratory behavior induced by moxonidine at mildly hypotensive doses. Brain Res 964:9-20
Ma, John K; Zhu, H E; Piletz, John E (2003) Effect of postmortem delay on imidazoline receptor-binding proteins in human and mouse brain. Ann N Y Acad Sci 1009:341-6
Zhu, H; Halaris, A; Piletz, J E (2003) Atypical [(3)H]clonidine binding sites in human caudate and platelets on cryostat-cut sections. Ann N Y Acad Sci 1009:296-301
Chen, Michael J; Zhu, H E; Piletz, John E (2003) Intracellular effect of imidazoline receptor on alpha(2A)-noradrenergic receptor. Ann N Y Acad Sci 1009:427-38
Zhu, H; Piletz, J E (2003) Association between I(2) binding sites and monoamine oxidase-B activity in platelets. Ann N Y Acad Sci 1009:347-52
Dontenwill, M; Pascal, G; Piletz, J E et al. (2003) IRAS, the human homologue of Nischarin, prolongs survival of transfected PC12 cells. Cell Death Differ 10:933-5

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