title: Inhibition of L-Type Ca2+Channels by TRPC1-STIM1 Complex Is Essential for the Protection of Dopaminergic Neurons.
abstract: Loss of dopaminergic (DA) neurons leads to Parkinson's disease; however, the mechanism(s) for the vulnerability of DA neurons is(are) not fully understood. We demonstrate that TRPC1 regulates the L-type Ca2+channel that contributes to the rhythmic activity of adult DA neurons in the substantia nigra region. Store depletion that activates TRPC1, via STIM1, inhibits the frequency and amplitude of the rhythmic activity in DA neurons of wild-type, but not in TRPC1-/-, mice. Similarly, TRPC1-/-substantia nigra neurons showed increased L-type Ca2+currents, decreased stimulation-dependent STIM1-Cav1.3 interaction, and decreased DA neurons. L-type Ca2+currents and the open channel probability of Cav1.3 channels were also reduced upon TRPC1 activation, whereas increased Cav1.3 currents were observed upon STIM1 or TRPC1 silencing. Increased interaction between Cav1.3-TRPC1-STIM1 was observed upon store depletion and the loss of either TRPC1 or STIM1 led to DA cell death, which was prevented by inhibiting L-type Ca2+channels. Neurotoxins that mimic Parkinson's disease increased Cav1.3 function, decreased TRPC1 expression, inhibited Tg-mediated STIM1-Cav1.3 interaction, and induced caspase activation. Importantly, restoration of TRPC1 expression not only inhibited Cav1.3 function but increased cell survival. Together, we provide evidence that TRPC1 suppresses Cav1.3 activity by providing an STIM1-based scaffold, which is essential for DA neuron survival.SIGNIFICANCE STATEMENTCa2+entry serves critical cellular functions in virtually every cell type, and appropriate regulation of Ca2+in neurons is essential for proper function. In Parkinson's disease, DA neurons are specifically degenerated, but the mechanism is not known. Unlike other neurons, DA neurons depend on Cav1.3 channels for their rhythmic activity. Our studies show that, in normal conditions, the pacemaking activity in DA neurons is inhibited by the TRPC1-STIM1 complex. Neurotoxins that mimic Parkinson's disease target TRPC1 expression, which leads to an abnormal increase in Cav1.3 activity, thereby causing degeneration of DA neurons. These findings link TRPC1 to Cav1.3 regulation and provide important indications about how disrupting Ca2+balance could have a direct implication in the treatment of Parkinson's patients.
authors.affiliation: Department of Biomedical Sciences, School of Medicine and Health Sciences, University of North Dakota, Grand Forks, North Dakota 58201, and.
authors.forename: Yuyang
authors.initials: Y
authors.lastname: Sun
authors.affiliation: Department of Biomedical Sciences, School of Medicine and Health Sciences, University of North Dakota, Grand Forks, North Dakota 58201, and.
authors.forename: Haopeng
authors.identifier: 0000-0002-2229-2927
authors.initials: H
authors.lastname: Zhang
authors.affiliation: Department of Biomedical Sciences, School of Medicine and Health Sciences, University of North Dakota, Grand Forks, North Dakota 58201, and.
authors.forename: Senthil
authors.initials: S
authors.lastname: Selvaraj
authors.affiliation: Department of Biomedical Sciences, School of Medicine and Health Sciences, University of North Dakota, Grand Forks, North Dakota 58201, and.
authors.forename: Pramod
authors.initials: P
authors.lastname: Sukumaran
authors.affiliation: Department of Biomedical Sciences, School of Medicine and Health Sciences, University of North Dakota, Grand Forks, North Dakota 58201, and.
authors.forename: Saobo
authors.initials: S
authors.lastname: Lei
authors.affiliation: National Institute of Environmental Health Sciences, Durham, North Carolina 27709.
authors.forename: Lutz
authors.initials: L
authors.lastname: Birnbaumer
authors.affiliation: Department of Biomedical Sciences, School of Medicine and Health Sciences, University of North Dakota, Grand Forks, North Dakota 58201, and brij.singh@med.und.edu.
authors.forename: Brij B
authors.identifier: 0000-0003-0535-5997
authors.initials: BB
authors.lastname: Singh
mesh_terms: D000818:Animals; D002118:Calcium / Q000378:metabolism; D020746:Calcium Channels, L-Type / Q000378:metabolism*; D020013:Calcium Signaling / Q000502:physiology*; D002470:Cell Survival / Q000502:physiology*; D002478:Cells, Cultured; D059290:Dopaminergic Neurons / Q000166:cytology / Q000473:pathology*; D015640:Ion Channel Gating / Q000502:physiology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D000071737:Stromal Interaction Molecule 1 / Q000378:metabolism*; D050052:TRPC Cation Channels / Q000378:metabolism*
chemical_list: C485995:Cacna1d protein, mouse; D020746:Calcium Channels, L-Type; C100757:Stim1 protein, mouse; D000071737:Stromal Interaction Molecule 1; D050052:TRPC Cation Channels; C096351:transient receptor potential cation channel, subfamily C, member 1; D002118:Calcium
keywords: Cav1.3; Parkinson's disease; SOCE; TRPC1-STIM1; calcium