Individuals with Parkinson's disease (PD) experience a progressive decline in motor function as a result of selective loss of dopaminergic (DA) neurons in the substantia nigra. The mechanism(s) underlying the loss of DA neurons is not known. Here, we show that a neurotoxin that causes a disease that mimics PD upon administration to mice, because it induces the selective loss of DA neurons in the substantia nigra, alters Ca 2+ homeostasis and induces ER stress. In a human neuroblastoma cell line, we found that endogenous store-operated Ca 2+ entry (SOCE), which is critical for maintaining ER Ca 2+ levels, is dependent on transient receptor potential channel 1 (TRPC1) activity. Neurotoxin treatment decreased TRPC1 expression, TRPC1 interaction with the SOCE modulator stromal interaction molecule 1 (STIM1), and Ca 2+ entry into the cells. Overexpression of functional TRPC1 protected against neurotoxin-induced loss of SOCE, the associated decrease in ER Ca 2+ levels, and the resultant unfolded protein response (UPR). In contrast, silencing of TRPC1 or STIM1 increased the UPR. Furthermore, Ca 2+ entry via TRPC1 activated the AKT pathway, which has a known role in neuroprotection. Consistent with these in vitro data, Trpc1 -/-mice had an increased UPR and a reduced number of DA neurons. Brain lysates of patients with PD also showed an increased UPR and decreased TRPC1 levels. Importantly, overexpression of TRPC1 in mice restored AKT/mTOR signaling and increased DA neuron survival following neurotoxin administration. Overall, these results suggest that TRPC1 is involved in regulating Ca 2+ homeostasis and inhibiting the UPR and thus contributes to neuronal survival.

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Summary The entorhinal cortex (EC) is regarded as the gateway to the hippocampus and thus is essential for learning and memory. Whereas the EC expresses a high density of GABAB receptors, the functions of these receptors in this region remain unexplored. Here we examined the effects of GABAB receptor activation on neuronal excitability in the EC and spatial learning. Application of baclofen, a specific GABAB receptor agonist, inhibited significantly neuronal excitability in the EC. GABAB receptor-mediated inhibition in the EC was mediated via activating TREK-2, a type of two-pore domain K+ channels and required the functions of inhibitory G proteins and protein kinase A pathway. Depression of neuronal excitability in the EC underlies GABAB receptor-mediated inhibition of spatial learning as assessed by Morris water maze. Our study indicates that GABAB receptors exert a tight control over spatial learning by modulating neuronal excitability in the EC.

Disturbances in Ca2+ homeostasis have been implicated in a variety of neuropathological conditions including Parkinson’s disease (PD). However, the importance of store-operated Ca2+ entry (SOCE) channels in PD remains to be investigated. In the present study, we have scrutinized the significance of TRPC1 in 1-methyl- 4-phenyl-1, 2, 3, 6 -tetrahyrdro-pyridine (MPTP)-induced PD using C57BL/6 animal model or PC12 cell culture model. Both sub-acute and sub-chronic treatments of MPTP significantly reduced TRPC1, and tyrosine hydroxylase levels, but not TRPC3, along with increased neuronal death. Furthermore, MPTP induces mitochondrial dysfunction, which was associated with reduced mitochondrial membrane potential, decreased level of Bcl2, Bcl-xl, and an altered Bcl-xl/Bax ratio thereby initiating apoptosis. Importantly, TRPC1 overexpression in PC12 cells showed significant protection against MPP+ induced neuronal apoptosis, which was attributed to the restoration of cytosolic Ca2+ and preventing loss of mitochondrial membrane potential. Silencing of TRPC1 or addition of TRPC1 channel blockers decreased mitochondrial membrane potential, whereas activation of TRPC1 restored mitochondrial membrane potential in cells overexpressing TRPC1. TRPC1 overexpression also inhibited Bax translocation to the mitochondria and thereby prevented cytochrome c release and mitochondrial mediated apoptosis. Overall, these results provide compelling evidence for the role of TRPC1 in either onset/progression of PD and restoration of TRPC1 levels could limit neuronal degeneration in MPTP mediated PD.

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