It is a common belief that voltage-gated calcium channels (VGCC) cannot carry toxic amounts of Ca2+ in
neurons. Also, some of them as L-type channels are essential for Ca2+-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 Ca2+ when: a)
their density or activity increases because of aging, chronic hypoxia or exposure to β-amyloid peptides or b) Ca2+-
dependent action potentials carry high Ca2+ loads in pacemaker neurons. Besides, we will examine conditions in which
VGCCs promote neuronal cell death without carrying excess Ca2+. This can happen, for instance, when they carry metal
ions into the neuronal cytoplasm or when a pathological decrease in their activity weakens Ca2+-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.
Keywords: Neurovascular unit, voltage-gated Ca2+ channels, neurodegeneration, beta-amyloid, Parkinson’s disease,
Alzheimer’s disease, Multiple Sclerosis.
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