Neurotrophins, such as NGF and BDNF, are prominent regulators of neuronal survival, growth and differentiation during development of the vertebrate nervous system. The actions of neurotrophins are dictated by two classes of cell surface receptors, the Trk receptor tyrosine kinases and the p75 neurotrophin receptor. After binding, neurotrophins and each of their receptors undergo internalization, intracellular trafficking and transport. In the last grant period, we studied the activation of Trk receptor tyrosine kinases via a G protein-coupled receptors (GPCR). Two GPCR ligands, adenosine and pituitary adenylate cydaseactivating polypeptide (PACAP), can activate Trk receptor activity to increase the survival of neural cells in the absence of neurotrophins. In contrast to neurotrophin treatment, the majority of activated Trk receptors were found in intracellular locations, such as Golgi and endosomal membranes. These results indicate that intracel lular trafficking of receptors plays an important role in their signaling outcomes. In the next grant period, we will test the hypothesis that proteins that regulate Trk receptor internalization, translocation and recycling are critical to our understanding of neurotrophin signaling. Both the biosynthetic and the endocytic pathways will be examined for their impact on Trk activity. Because the localization of neurotrophin receptors is critical to neuronal cell survival and plasticity, our investigation is directly relevant to the understanding and treatment of neurodegenerative diseases, such as amyotrophic lateral sclerosis, Huntington's and Alzheimer's diseases.
Neurotrophins have been proposed as therapeutic agents for many neurodegenerative disorders, such as Alzheimer's and Huntington's diseases. For example, NGF and BONF have potent activities on many neuronal populations that are critical in Alzheimer's disease. Administration of neurotrophins is effective in stopping or delaying the progression of the disease. However. human clinical efforts using NGF, BONF and NT-3 have met with disappointing results, due in part to difficulties of delivery and and unanticipated side effects. We have discovered an alternative way of activating Trk neurotrophin receptors through small molecules that interact with G proteincoupled receptors and glucocorticoid receptors. We found that neurotrophin receptors can signal in intracellular locations in neurons. Therefore, an understanding of the trafficking and signaling of neurotrophin receptors will indicate new ways of maintaining neuronal cell survival and increasing synaptic plasticity in the adult nervous system.
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