Inhibition of L-Type Ca 2+ Channels by TRPC1-STIM1 Complex Is Essential for the Protection of Dopaminergic Neurons

• Published in: The Journal of neuroscience 2017-03, Vol.37 (12), p.3364-3377
• Main Authors: Sun, Yuyang, Zhang, Haopeng, Selvaraj, Senthil, Sukumaran, Pramod, Lei, Saobo, Birnbaumer, Lutz, Singh, Brij B
• Format: Article
• Language: English
• Subjects: Animals; Calcium - metabolism; Calcium Channels, L-Type - metabolism; Calcium Signaling - physiology; Cell Survival - physiology; Cells, Cultured; Dopaminergic Neurons - cytology; Dopaminergic Neurons - pathology; Ion Channel Gating - physiology; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Stromal Interaction Molecule 1 - metabolism; TRPC Cation Channels - metabolism
• ISSN: 0270-6474; 1529-2401
• DOI: 10.1523/JNEUROSCI.3010-16.2017

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 Ca 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 Ca currents, decreased stimulation-dependent STIM1-Ca 1.3 interaction, and decreased DA neurons. L-type Ca currents and the open channel probability of Ca 1.3 channels were also reduced upon TRPC1 activation, whereas increased Ca 1.3 currents were observed upon STIM1 or TRPC1 silencing. Increased interaction between Ca 1.3-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 Ca channels. Neurotoxins that mimic Parkinson's disease increased Ca 1.3 function, decreased TRPC1 expression, inhibited Tg-mediated STIM1-Ca 1.3 interaction, and induced caspase activation. Importantly, restoration of TRPC1 expression not only inhibited Ca 1.3 function but increased cell survival. Together, we provide evidence that TRPC1 suppresses Ca 1.3 activity by providing an STIM1-based scaffold, which is essential for DA neuron survival. Ca entry serves critical cellular functions in virtually every cell type, and appropriate regulation of Ca 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 Ca 1.3 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 Ca 1.3 activity, thereby causing degeneration of DA neurons. These findings link TRPC1 to Ca 1.3 regulation and provide important indications about how disrupting Ca balance could have a direct implication in the treatment of Parkinson's patients.