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-Ca(v)1.3 interaction, and decreased DA neurons. L-type Ca2+ currents and the open channel probability of Ca(v)1.3 channels were also reduced upon TRPC1 activation, whereas increased Ca(v)1.3 currents were observed upon STIM1 or TRPC1 silencing. Increased interaction between Ca(v)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 Ca2+ channels. Neurotoxins that mimic Parkinson's disease increased Ca(v)1.3 function, decreased TRPC1 expression, inhibited Tg-mediated STIM1-Ca(v)1.3 interaction, and induced caspase activation. Importantly, restoration of TRPC1 expression not only inhibited Ca(v)1.3 function but increased cell survival. Together, we provide evidence that TRPC1 suppresses Ca(v)1.3 activity by providing an STIM1-based scaffold, which is essential for DA neuron survival.