Dopaminergic neurons receive excitatory input from glutamatergic neurons. Excitation results in Ca²⁺ influx across the plasma membrane through NMDA receptors. Ca²⁺ is transported into the ER and mitochondria. In response to either IP₃ or elevated cytosolic Ca²⁺ levels, Ca²⁺ is released from the ER through IP₃ or ryanodine receptor channels. ER Ca²⁺ stores are replenished by SOCE, a process in which STIM1 interacts with TRPC1 Ca²⁺ channels in the plasma membrane, resulting in Ca²⁺ influx. Much of the Ca²⁺ that enters through TRPC1 channels is transported into the ER, replenishing the ER Ca²⁺ pool. SOCE may also lead to activation of AKT, which, in turn, activates mTOR. In this issue of the JCI, Selvaraj et al. (6) reveal a role for impaired SOCE in the degeneration of dopaminergic neurons caused by the mitochondrial toxin MPTP. MPP⁺, a metabolite of MPTP, is transported into dopaminergic neurons via the dopamine transporter protein (DAT) and then interacts with and inhibits complex I in the mitochondrial electron transport chain. This results in excessive generation of superoxide and dysregulation of mitochondrial Ca²⁺ regulation. One consequence of these mitochondrial alterations is suppression of expression of the Trpc1 gene, resulting in impaired SOCE, ER Ca²⁺ store depletion, and activation of the UPR. If strong and sustained, the UPR can trigger a programmed cell death (PCD) pathway involving the proteins activating transcription factor 4 (ATF4) and CHOP. CytC, cytochrome c; PTP, permeability transition pore.