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. Parkinson's disease (PD) is a progressive neurodegenerative disorder associated with selective loss of dopaminergic neurons in the substantia nigra pars compacta. A number of pathogenic factors have been implicated in the degeneration of dopaminergic neurons in the substantia nigra including generation of free radicals, impairment of mitochondrial function, disturbances of calcium homeostasis, and apoptosis. It could be hypothesized that a common factor should be involved in the pathogenesis of PD. Calcium being a common factor in all the above processes raises the possibility that this could be the possible link. Also calcium homeostasis plays an important role in stimulating and inhibiting neuronal cell death, and calcium mediates apoptosis. Thus, depending on spatial and temporal factors, calcium channels may have a salutary effect on conditions such as PD in which apoptosis may be the ultimate mode of cell death. Calcium enters the cytoplasm from two sources; it is either released from the intracellular stores, or it enters through the plasma membrane. Depletion of the intracellular stores leads to the opening of plasma membrane calcium channels which are known as store-operated calcium entry (SOCE) channels. Recently, a mammalian homologue of the Drosophila trp gene, TRPC1, has been suggested as a SOCE channel. Moreover, our recent data indicate that TRPC1 protein levels and its plasma membrane localization is significantly decreased after treatment with drugs known to cause PD (MPP+ or salsolinol). Importantly, overexpression of TRPC1 protected SH-SY5Y neuronal cells against the cellular toxicity elicited by MPP+ and salsolinol. The protection exhibited by TRPC1 was dependent on its calcium influx properties and the translocation of pro-apoptotic proteins from the endoplasmic reticulum to mitochondria. These data demonstrate, for the first time, that TRPC1 has a role in protecting dopaminergic neurons. Nevertheless, the role of TRPC1 in vivo has yet to be elucidated and the mechanisms by which TRPC1 protects dopaminergic neurons are not known. Thus, we propose to extend our knowledge in animal models (TRPC1 knockout mice, and PD mouse models) and determine the role of TRPC1 in PD by identifying mechanism(s) by which TRPC1 protects dopaminergic neurons.