Roles for the Endoplasmic Reticulum in Regulation of Neuronal Calcium Homeostasis

By influencing Ca²⁺ homeostasis in spatially and architecturally distinct neuronal compartments, the endoplasmic reticulum (ER) illustrates the notion that form and function are intimately related. The contribution of ER to neuronal Ca²⁺ homeostasis is attributed to the organelle being the largest reservoir of intracellular Ca²⁺ and having a high density of Ca²⁺ channels and transporters. As such, ER Ca²⁺ has incontrovertible roles in the regulation of axodendritic growth and morphology, synaptic vesicle release, and neural activity dependent gene expression, synaptic plasticity, and mitochondrial bioenergetics. Not surprisingly, many neurological diseases arise from ER Ca²⁺ dyshomeostasis, either directly due to alterations in ER resident proteins, or indirectly via processes that are coupled to the regulators of ER Ca²⁺ dynamics. In this review, we describe the mechanisms involved in the establishment of ER Ca²⁺ homeostasis in neurons. We elaborate upon how changes in the spatiotemporal dynamics of Ca²⁺ exchange between the ER and other organelles sculpt neuronal function and provide examples that demonstrate the involvement of ER Ca²⁺ dyshomeostasis in a range of neurological and neurodegenerative diseases.