The endoplasmic reticulum and junctional membrane communication during calcium signaling

• The endoplasmic reticulum is the largest Ca2 + store in eukaryotic cells.
• Organelles contain transport mechanisms for Ca2 + uptake and release, and luminal Ca2 + buffering.
• ER Ca2 + stores can be mobilized by intracellular messengers.
• The ER makes membrane contacts with the plasma membrane and other Ca2 + storage organelles.
• ER junctions, formed by tethering molecules, are the sites of major Ca2 + signaling processes.

The endoplasmic reticulum is a major organelle in all eukaryotic cells which performs multiple functions including protein and lipid synthesis and sorting, drug metabolism, and Ca2 + storage and release. The endoplasmic reticulum, and its specialized muscle counterpart the sarcoplasmic reticulum, is the largest and most extensive of Ca2 + storage organelle in eukaryotic cells, often occupying in excess of 10% of the cell volume. There are three major components of Ca2 + storage organelles which mediate their major functions: Ca2 + uptake, mediated by pumps and exchangers; storage enhanced by luminal Ca2 + binding proteins, and Ca2 + mobilization mediated by specific ion channels. Ca2 + mobilization from the endoplasmic reticulum plays a central role in Ca2 + signaling. Through Ca2 + release channels in its membrane, the pervading and plastic structure of the endoplasmic reticulum allows Ca2 + release to be rapidly targeted to specific cytoplasmic sites across the whole cell. That several endoplasmic reticulum Ca2 + release channels are also activated by Ca2 + itself, contributes to endoplasmic reticulum membrane excitability which is the principal basis for generating spatio-temporal complex cellular Ca2 + signals, allowing specific processes to be regulated by this universal messenger. In addition, the endoplasmic reticulum forms discrete junctions with the plasma membrane and membranes of organelles such as mitochondria and lysosomes, forming nanodomains at their interfaces that play critical roles in Ca2 + signaling during key cellular processes such as cellular bioenergetics, apoptosis and autophagy. At these junctions key Ca2 + transport and regulatory processes come into play, and a recurring theme in this review is the often tortuous paths in identifying these mechanisms unequivocally. This article is part of a Special Issue entitled: Functional and structural diversity of endoplasmic reticulum.