Inhibition of L-type Ca2+ channels by TRPC1-STIM1 complex is essential for the protection of dopaminergic neurons

Yuyang Sun, Haopeng Zhang, Senthil Selvaraj, Pramod Sukumaran, Saobo Lei, Lutz Birnbaumer, Brij B. Singh

Research output: Contribution to journalArticlepeer-review

32 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)3364-3377
Number of pages14
JournalJournal of Neuroscience
Volume37
Issue number12
DOIs
StatePublished - Mar 22 2017

Keywords

  • Calcium
  • Cav1.3
  • Parkinson’s disease
  • SOCE
  • TRPC1-STIM1

ASJC Scopus subject areas

  • Neuroscience(all)

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