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

Mauro      Cataldi

doi:10.2174/1570159X11311030004

Abstract

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.