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It is a common belief that voltage-gated calcium channels (VGCC) cannot carry toxic amounts of Ca(2+) in neurons. Also, some of them as L-type channels are essential for Ca(2+)-dependent regulation of prosurvival gene-programs. However, a wealth of data show a beneficial effect of drugs acting on VGCCs in several neurodegenerative and neurovascular diseases. In the present review, we explore several mechanisms by which the "harmless" VGCCs may become "toxic" for neurons. These mechanisms could explain how, though usually required for neuronal survival, VGCCs may take part in neurodegeneration. We will present evidence showing that VGCCs can carry toxic Ca(2+) when: a) their density or activity increases because of aging, chronic hypoxia or exposure to β-amyloid peptides or b) Ca(2+)-dependent action potentials carry high Ca(2+) loads in pacemaker neurons. Besides, we will examine conditions in which VGCCs promote neuronal cell death without carrying excess Ca(2+). This can happen, for instance, when they carry metal ions into the neuronal cytoplasm or when a pathological decrease in their activity weakens Ca(2+)-dependent prosurvival gene programs. Finally, we will explore the role of VGCCs in the control of nonneuronal cells that take part to neurodegeneration like those of the neurovascular unit or of microglia.

The Changing Landscape of Voltage-Gated Calcium Channels in Neurovascular Disorders and in Neurodegenerative Diseases