Considerable evidence, including recent direct observations, suggest that endoplasmic reticulum (ER) Ca(2+) stores in neurons, glia, and other cell types, consists of spatially-distinct compartments that can be individually loaded and unloaded. In addition, sub-plasmalemmal ('junctional') components of the ER (jER) are functionally coupled to the overlying plasmalemmal (PL) microdomains in PL-jER units named 'PLasmERosomes'. The PL microdomains and the jER contain clusters of specific transport proteins that regulate Na(+) and Ca(2+) concentrations in the tiny cytosolic space between the PL and jER. This organization helps the ER to produce the many types of complex local and global Ca(2+) signals that are responsible for the simultaneous control of numerous neuronal and glial functions.