Potential physiological and pathological roles for axonal ryanodine receptors.

Clinical disability following trauma or disease to the spinal cord often involves the loss of vital white matter elements including axons and glia. Although excessive Ca is an established driver of axonal degeneration, therapeutically targeting externally sourced Ca to date has had limited success in both basic and clinical studies. Contributing factors that may underlie this limited success include the complexity of the many potential sources of Ca entry and the discovery that axons also contain substantial amounts of stored Ca that if inappropriately released could contribute to axonal demise. Axonal Ca storage is largely accomplished by the axoplasmic reticulum that is part of a continuous network of the endoplasmic reticulum that provides a major sink and source of intracellular Ca from the tips of dendrites to axonal terminals. This "neuron-within-a-neuron" is positioned to rapidly respond to diverse external and internal stimuli by amplifying cytosolic Ca levels and generating short and long distance regenerative Ca waves through Ca induced Ca release. This review provides a glimpse into the molecular machinery that has been implicated in regulating ryanodine receptor mediated Ca release in axons and how dysregulation and/or overstimulation of these internodal axonal signaling nanocomplexes may directly contribute to Ca-dependent axonal demise. Neuronal ryanodine receptors expressed in dendrites, soma, and axonal terminals have been implicated in synaptic transmission and synaptic plasticity, but a physiological role for internodal localized ryanodine receptors remains largely obscure. Plausible physiological roles for internodal ryanodine receptors and such an elaborate internodal binary membrane signaling network in axons will also be discussed.