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

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.

The Marine Guanidine Alkaloid Crambescidin 816 Induces Calcium Influx and Cytotoxicity in Primary Cultures of Cortical Neurons through Glutamate Receptors

“…44,45 It must be pointed out that although it is generally assumed that voltage gated calcium channels do not carry toxic amounts of Ca 2+ into neurons, it has been recently described that VGCC may take part in neurodegeneration by inducing calcium loads into neurons. 46 However, in our conditions, the L-type calcium channel blocker NIF did not impede the calcium influx elicited by Cramb816, therefore indicating that the increase in calcium elicited by Cramb816 was not mediated by VGCC. Furthermore, the fact that the calcium influx was higher in younger than in older cortical neurons was also in contradiction with a calcium influx through L-type calcium channels since it is well-known that L-type calcium currents are larger in older neurons 47 which are more vulnerable to death in an L-type channel dependent manner.…”

Dendritic and axonal mechanisms of Ca2+ elevation impair BDNF transport in Aβ oligomer–treated hippocampal neurons

“…This may be attributed to a novel, presynaptic mechanism of AβO-induced Ca 2+ dysregulation that converges on postsynaptic mechanisms of CaN activation to impair FAT. Although AβOs are believed to bind exclusively to dendritic membrane proteins ( Cochran et al ., 2013 ), in vitro and in vivo evidence suggests that AβOs also modulate presynaptic VGCC activity ( Cataldi, 2013 ). If Ca 2+ elevation is restricted to the cell body and dendrites by extensive buffering mechanisms, axonal AβO binding may induce aberrant Ca 2+ influx through VGCCs and contribute to FAT impairment.…”

Ca2+homeostasis dysregulation in Alzheimer's disease: a focus on plasma membrane and cell organelles

“…Although 2 large-population, long-term cohort studies have proved the protective role of calcium channel blockers rather than other types of antihypertensive drugs on the risk of dementia among elderly hypertensive population (77,78), the clinical effect of each specific L-type VGCC blocker remains controversial (79)(80)(81). Therefore, the AD-related alteration of L-type VGCC in different brain regions, as well as the distinct mechanisms and influences of different blockers [partly reviewed in Cataldi (82)], still need intensive study. In view of the probable memory-promotion action of L-type calcium signal, safety of the blockers in clinical usage should also be brought into consideration.…”