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 Ca2+ 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 Ca2+ buffering, leads to large somatodendritic fluctuations of intracellular Ca2+ levels that are linked to elevated mitochondrial
oxidant stress. L-type voltage-gated Ca2+ channels (LTCCs) contribute to these Ca2+ oscillations in dendrites, and LTCC inhibition was beneficial in cellular and in vivo 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 Ca2+ 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 Ca2+ 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 Ca2+ oscillations) during pacemaking.