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    NEUROPEPTIDE Y RECEPTOR TYPE 5 AS A REGULATORY RECEPTOR IN NPY SYSTEM

    Cover for NEUROPEPTIDE Y RECEPTOR TYPE 5 AS A REGULATORY RECEPTOR IN NPY SYSTEM
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    Creator
    Czarnecka, Magdalena K.
    Advisor
    Kitlinska, Joanna B
    Sherman, Thomas G
    Abstract
    Neuropeptide Y (NPY) is one of the most abundant peptides in the central and peripheral nervous system. It is involved in numerous physiological (e.g. energy and bone homeostasis) and pathophysiological processes (e.g. atherosclerosis, cancer). Its functions are predominantly mediated by Y1, Y2 and Y5 receptors. While Y1 and Y2 receptors are well characterized, functions of the Y5 receptors (Y5Rs) are not fully elucidated.
     
    Y5R is usually co-expressed with other NPY receptors at low levels, often in an inducible manner. In this thesis, it is hypothesized that Y5R plays a regulatory role in the NPY system.
     
    Indeed, here we have shown that co-expression of Y5 with Y1 receptors sensitized CHO-K1 cells to NPY and triggered the mitogenic response to the peptide at picomolar concentrations. This high affinity peak of activity, which was not observed in the cells expressing single receptors, was blocked by Y1 and Y5 receptor antagonists. These results indicate that both receptors need to be activated for this effect and suggest Y1/Y5 receptor interactions. In line with this, immunoprecipitation experiments revealed the presence of Y1/Y5 receptor heterodimers.
     
    Next to their direct interactions with other NPY receptors, Y5Rs are involved in cross-talk with tyrosine kinase receptors (RTKs) for brain-derived neurotrophic factor (BDNF) - TrkB. In neuroblastoma cells constitutively expressing only Y2 receptors (Y2Rs), BDNF additionally induced expression of Y5Rs. Interestingly, it was Y2R, not Y5R or Y2/Y5 receptors blockade, which completely suppressed the proliferative effect of NPY in neuroblastoma cells. Instead, the Y5Rs seem to modify signaling of TrkB. Y5R antagonists markedly reduced BDNF-induced TrkB phosphorylation and p44/42 MAPK activation. These interactions between Y5R and TrkB signaling pathways had also functional consequences. Blocking Y5Rs significantly decreased BDNF-driven neuroblastoma cell survival and impaired the acquisition of resistance to chemotherapy, while combining Y5R and Trk antagonists completely abolishes pro-survival effect of BDNF.
     
    In summary, Y5R is a potent modulatory receptor interacting with other NPY receptors, and RTKs. Such interactions of the Y5Rs enhance functions of NPY and enable cross-talk of the NPY system with other pathways. Understanding the mechanisms and functional consequences of Y5R activity may open new therapeutic opportunities for NPY-associated disorders.
     
    Description
    Ph.D.
    Permanent Link
    http://hdl.handle.net/10822/558411
    Date Published
    2012
    Subject
    BDNF; GPCR; neuroblastoma; neuropeptide Y; NPY Y5R; TrkB; Physiology; Biochemistry; Physiology; Biochemistry;
    Type
    thesis
    Publisher
    Georgetown University
    Extent
    148 leaves
    Collections
    • Graduate Theses and Dissertations - Physiology & Biophysics
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      The Role of Neuropeptide Y and Its Y5R Receptor in RHOA-Mediated Regulation of Cell Motility and Cytokinesis: Implications for Cancer Metastasis 

      Alsaud, Nouran Abu (Georgetown University, 2020)
      Neuropeptide Y (NPY) and its Y5 receptor (Y5R) are expressed in a number of malignancies, including pediatric tumors neuroblastoma (NB) and Ewing sarcoma (ES). Our previous clinical and experimental data implicated NPY/Y5R ...
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    Georgetown University Seal
    ©2009 - 2023 Georgetown University Library
    37th & O Streets NW
    Washington DC 20057-1174
    202.687.7385
    digitalscholarship@georgetown.edu
    Accessibility