This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. The neurotrophins, NGF, BDNF, NT-3 and NT-4, are essential for the development of the vertebrate nervous system, as well as changes in synaptic plasticity. Each neurotrophin can signal through two different cell surface receptors, Trk receptor tyrosine kinases and the p75 neurotrophin receptor. The biological effects of neurotrophins require that signals are conveyed over long distances from the nerve terminal to the cell body and also to specialized synaptic structures. We have been investigating several cytoplasmic proteins which are associated with the BDNF TrkB receptor in neurons. BDNF plays a critical role in synaptic transmission and plasticity and has been implicated in cognitive function and mood disorders, such as depression and schizophrenia. BDNF can stimulate neurotransmitter release through its receptor tyrosine kinase, TrkB, but the molecular components involved in neurotrophin-mediated synaptic transmission are largely unknown. We have found that the actin-based motor, myosin VI, and a myosin VI-binding protein, GIPC, form a complex that can engage TrkB. BDNF-induced glutamate release from presynaptic terminals not only depends upon TrkB, but was abolished in hippocampal neurons lacking myosin VI or GIPC. Myosin VI is a minus-end-directed actin-based motor found in several neuronal populations that express Trk neurotrophin receptors. These results define an essential role for the myosin VI-GIPC motor complex in BDNF-TrkB-mediated presynaptic function.
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