TRPC1 inhibits apoptotic cell degeneration induced by dopaminergic neurotoxin MPTP/MPP+

Abstract

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.

Neurotoxin-induced ER stress in mouse dopaminergic neurons involves downregulation of TRPC1 and inhibition of AKT/mTOR signaling

“…In particular, recent studies have shed light on the neuroprotective effect of TRPC channels in the SNpc against Tat neurotoxicity (49). Our previous studies also show the neuroprotective action of TRPC1 against in vitro cell culture models of PD (19); however, the precise mechanisms by which TRPC1 regulates neuronal survival remained poorly understood. In this study, we showed that TRPC1 overexpression confers protection against ER stress in both in vivo and in vitro models of PD.…”

“…Proteins were resolved in 4%-12% NuPAGE gels, followed by Western blotting with the desired antibodies. Crude membrane or lysates were prepared from SH-SY5Y cells and from animal and human tissues as previously described (18,19). Protein concentrations were determined using the Bradford reagent (Bio-Rad), and 25-50 μg of lysates were resolved on NuPAGE 4%-12% Bis-Tris gel or NuPAGE 3%-8% Tris-acetate gels (Invitrogen), followed by Western blotting as described in refs.…”

“…However, although it is apparent that ER stress plays a major role in neurodegeneration, the mechanism by which these neurotoxins induce ER stress is not known. Previously we reported that transient receptor potential channel 1 (TRPC1) is critical for neuronal survival and that MPP + treatment decreases TRPC1 expression in SH-SY5Y and PC12 cells (18,19); however, the mechanism is not known.…”

Ion channels in cancer: future perspectives and clinical potential

“…TRP channels are expressed in tumours [62]. Ca 2þ entry through TRP channels may inhibit apoptosis [63,64], an effect partially attributed to the stimulation of NF-kB [64]. Moreover, TRPP2 channels may, by an increase in the endoplasmatic reticulum Ca 2þ permeability, deplete Ca 2þ stores thus blunting the intracellular Ca 2þ release upon apoptotic stimuli [4,65].…”

Docosahexaenoic acid provides protective mechanism in bilaterally MPTP-lesioned rat model of Parkinson's disease

“…MPTP is a potent neurotoxin that selectively destroys the nigrostriatal dopaminergic neurons in humans, sub-human primates, and lower animals [12][13][14]. MPTP is a highly lipophilic compound and can cross the blood brain barrier [15].…”