Voltage-Gated Ca Channels in Dopaminergic Substantia Nigra Neurons: Therapeutic Targets for Neuroprotection in Parkinson's Disease?

The loss of dopamine (DA)-producing neurons in the substantia nigra pars compacta (SN) underlies the core motor symptoms of the progressive movement disorder Parkinson's disease (PD). To date, no treatment to prevent or slow SN DA neurodegeneration exists; thus, the identification of the underlying factors contributing to the high vulnerability of these neurons represents the basis for the development of novel therapies. Disrupted Ca homeostasis and mitochondrial dysfunction seem to be key players in the pathophysiology of PD. The autonomous pacemaker activity of SN DA neurons, in combination with low cytosolic Ca buffering, leads to large somatodendritic fluctuations of intracellular Ca levels that are linked to elevated mitochondrial oxidant stress. L-type voltage-gated Ca channels (LTCCs) contribute to these Ca oscillations in dendrites, and LTCC inhibition was beneficial in cellular and animal models of PD. However, in a recently completed phase 3 clinical trial, the dihydropyridine (DHP) LTCC inhibitor isradipine failed to slow disease progression in early PD patients, questioning the feasibility of DHPs for PD therapy. Novel evidence also suggests that R- and T-type Ca channels (RTCCs and TTCCs, respectively) represent potential PD drug targets. This short review aims to (re)evaluate the therapeutic potential of LTCC, RTCC, and TTCC inhibition in light of novel preclinical and clinical data and the feasibility of available Ca channel blockers to modify PD disease progression. I also summarize their cell-specific roles for SN DA neuron function and describe how their gating properties allow activity (and thus their contribution to stressful Ca oscillations) during pacemaking.