FUNCTIONS OF STORE-OPERATED CALCIUM CHANNELS

Abstract

In most eukaryotic cells, calcium signaling occurs through an interacting combination of intracellular calcium release and entry of calcium across the plasma membrane. Although various mechanisms can subtend these processes, the most widely encountered mechanisms are intracellular calcium release via the inositol trisphosphate receptor, and entry of calcium through store-operated channels. Storeoperated calcium entry, as the name implies, involves activation of plasma membrane channels in response to a loss of calcium from intracellular endoplasmic (or sarcoplasmic) reticulum stores. The calcium level in the endoplasmic reticulum is sensed by either of two transmembrane calcium-binding proteins, STIM1 or STIM2. When calcium dissociates from the luminal binding site on STIM1 or 2, the protein aggregates and translocates to sites of close apposition of endoplasmic reticulum and plasma membranes. There, STIM recruits and binds hexameric calcium channels composed of Orai1 subunits (or possibly Orai2 or Orai3). This results in activation of the channels and accelerated entry of calcium into the cytoplasm.

The general function of store-operated calcium entry is the activation of downstream signaling mechanisms linked to processes ranging from contraction and secretion to cell growth and differentiation. The development of genetically modified mouse models with global or directed knockout of either STIM or Orai genes has provided significant information on the specific physiological processes that depend on this signaling mechanism. Among these processes are male fertility, neutrophil chemotaxis, and exocrine secretion. These and other aspects of the functions of storeoperated calcium channels will be the focus of this lecture.