The role of intracellular free calcium in motor neuron disease.

The intracellular calcium (Ca2+) concentrations of motoneurons can be altered by the influx of Ca2+ into the cell by the opening of voltage-dependent Ca2+ channels and ligand-gated channels linked to Ca2+ influx, especially by the N-methyl-D-aspartate (NMDA) type of excitatory amino acid receptor. Intracellular Ca2+ concentration is also affected by the release of Ca2+ buffered in mitochondria and endoplasmic reticulum. Evidence that motoneurons may be selectively vulnerable to Ca(2+)-induced cell death include the following observations: (i) the presence of excitatory amino acid receptors on the cell membranes of motoneurons, some of which would permit Ca2+ influx (e.g. NMDA receptors); (ii) the availability of the presynaptic terminal for antibody-mediated effects leading to changes in cell permeability and Ca2+ influx; and (iii) the limited amounts of intracellular Ca(2+)-binding proteins such as calbindin D28K and parvalbumin in motoneurons. Elevation of intracellular free Ca2+ may also be a common event in a number of independent mechanisms leading to motoneuron death in motor neuron disease.