TRPM7, a Ca2+ permeable nonselective cation channel, is linked to neurodegenerative diseases, and a human TRPM7 mutation has been identified in Parkinson's diseases (PD), suggesting its critical role in neurodegeneration. Published work has implied that neuronal death during anoxia and ischemia may be attributed to Ca2+ overflow via TRPM7. However, roles of TRPM7 in neurons remain undefined at physiological conditions. Biochemical studies demonstrate that TRPM7 is concentrated on synaptic vesicles and interacts with vesicular proteins, indicating that TRPM7 may be a critical player in synaptic vesicle recycling. Although vesicular TRPM7 may provide counterions for release of positively charged acetylcholine during exocytosis in sympathetic neurons, TRPM7 is also widely distributed in areas with negatively charged glutamate and neutral GABA as dominant neurotransmitters, suggesting a separate function in these regions. Therefore, the physiological function of presynaptic TRPM7 in the brain remains largely unknown. Our preliminary data presented in the research strategy strongly suggest that TRPM7 is the main conduit for Ca2+ influx in endocytosis, leading us to hypothesize that vesicular TRPM7 serves as the Ca2+ channel for synaptic vesicle endocytosis. We will test this hypothesis by using a combination of biophysical, live-cell imaging, and molecular biology techniques. Our goal is to clearly define, for the first time, the role of TRPM7 in endocytosis. Our studies will have profound implications for understanding the mechanisms of normal neuronal endocytic processes, how dysfunctions in these processes lead to neurodegenerative disease, and for development of new therapies to treat diseases with malfunctions in synaptic vesicle recycling and/or TRPM7.
The proposed research is relevant to public health because the discovery of evolutionarily conserved mechanisms is ultimately expected to increase the understanding of the pathogenesis of human disorders with malfunctions of synaptic vesicle endocytosis or TRPM7 channels such as Parkinson's disease, epilepsy, Alzheimer's disease and so on, as well as risk prediction for such abnormalities. Thus, the proposed research is relevant to the part of NIH's mission that pertains to developing fundamental knowledge that will help to reduce the burdens of human disability.
