Several non-receptor tyrosine kinases (nRTK) are highly expressed in the brain and are pivotal for brain functions and some mental diseases. Among brain-enriched nRTKs, Fyn draws the most attention. Recently, we found that Fyn directly binds to metabotropic glutamate receptor 5 (mGluR5), which enables Fyn to phosphorylate mGluR5 at a tyrosine site in the intracellular C-terminus (CT). These findings for the first time reveal mGluR5 as a direct substrate of Fyn. Encouraged by this new discovery, we propose this renewal application to further study the Fyn regulation of mGluR5 and to define roles of Fyn and mGluR1/5 in the pathogenesis and symptomology of a common mental illness. Our hypothesis is that Fyn binds and phosphorylates mGluR1/5 to control receptor function and promote depression-like behaviors. Using multidisciplinary approaches, this hypothesis will be tested both in vitro and in vivo, as appropriate, in the following four inter-supportive Aims.
Aim will characterize fundamental kinase-substrate biochemistry between Fyn and mGluR1/5 in vitro.
Aim II will define the regulation of Fyn-mGluR1/5 interactions and tyrosine phosphorylation of mGluR1/5 by changing dopamine inputs in striatal neurons in vivo.
Aim III will explore functional roles of Fyn-mediated phosphorylation in the modulation of trafficking and subcellular expression of mGluR1/5 and the efficacy of receptor signaling in striatal neurons.
Aim I V will firs monitor neuroadaptations of striatal Fyn-mGluR1/5 interactions and mGluR1/5 phosphorylation in response to prolonged social isolation in adult rats, a chronic stress paradigm modeling anhedonic depression in adulthood animals.
Aim I V will then clarify the functional role of Fyn-mGluR1/5 interactions in isolation-induced depression-like behaviors. Results achieved here will conceptually advance our current understanding of the phosphorylation-dependent regulation of glutamate receptor signaling. They will also ultimately contribute to the development of novel pharmacotherapies, by targeting an nRTK (Fyn) and mGluR1/5, for the treatment of some core symptoms of depression.
This research project is aimed to explore a novel and phosphorylation-dependent mechanism for the regulation of metabotropic glutamate receptors and to define the role of metabotropic glutamate receptors in the pathophysiology and symptomology of a common mental illness (major depression). The information obtained through this project is valuable for advancing the knowledge on biology of glutamate receptors related to depression and for the development of new pharmacotherapies for preventing and treating depressive disorders.
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