Adding insult to injury-molecular and functional perturbations of voltage-dependent calcium channel expression in disease

Abstract

VDCC (voltage-dependent calcium channels) play a central role as scaffolding proteins for the binding of synaptic vesicle and presynaptic membrane proteins. In addition to spatial constraints imposed by the localization of VDCC, the calcium that enters neurons via VDCC is exquisitely regulated kinetically leading to the formation of "microdomains" that extend from the mouth of the VDCC to a distance of approximately 50 nm in radius. Experimental access to this nanoscale domain has been limited. Recently, the importance of VDCC to normal neuronal function has been underscored by the identification of genetic lesions in specific VDCC subunits that lead to inherited forms of neuropathies in humans and mice. The primary defect is often coupled to downstream compensatory effects that result in the altered pattern of expression of non-mutated VDCC subunits. However, the connection between the molecular defects that arise within these microdomains as a consequence of mutated VDCC subunits and the ensuing neuropathy is not well established. We present recent biophotonic advances that afford experimental access and insight into this nanoscale microdomain. Furthermore we present novel molecular and biochemical probes that offer detailed analysis of the pattern of VDCC subunit expression and function in normal and diseased neurons. We anticipate that this high-resolution molecular analysis will delineate features that can serve as both diagnostic signatures of disease as well as potential therapeutic targets.