Calcium and liver

Abstract

Cells expand energy to lower the concentration of free calcium in the cytosol ([Ca2+]i) to a very low level. Extracellular Ca2+ entering via channels situated in the plasma membrane is expelled into the extracellular medium by a Ca(2+)-Mg(2+)-ATPase or by Na(+)-Ca2+ exchangers. The Ca2+ that enters the cell is sequestered, once inside the cytosol, by a Ca(2+)-Mg(2+)-ATPase, which concentrates Ca2+ in specialized domains of the endoplasmic reticulum. The nucleus and the mitochondria also concentrate Ca2+, but less efficiently. The stimulation of numerous receptors by hormones, growth factors and neurotransmitters coupled to GTP-binding proteins provokes a rapid increase in [Ca2+]i by mobilizing Ca2+ from intra- and extracellular compartments. Membrane coupling is ensured by the activation of a phospholipase C-beta, which hydrolyses a doubly phosphorylated phosphoinositide, phosphatidylinositol 4,5-bisphosphate (PtdIns(4,5)P2). The inositol (1,4,5)-trisphosphate (InsP3) consequently formed binds to a receptor consisting in 4 homologous of 250 kDa each. The InsP3 receptor has been localized to a specialized region, rich in Ca2+, of the endoplasmic reticulum. The receptor has been purified and its sequence obtained. Reincorporated into planar bilayers, it displays the properties of a channel. In the cell, opening of the InsP3 receptor-channel provokes the release of the Ca2+ accumulated within the endoplasmic reticulum. Analyzing the kinetics of channel opening by the methods of rapid mixing, rapid filtration or flash photolysis of caged InsP3 has revealed that InsP3 opens the channel within a very short time, probably less than 30 msec. The InsP3 receptor-channel is autoregenerative. With the sustained stimulation of a Ca2+ influx the release of Ca2+ leads to an augmentation of [Ca2+]i, which is responsible for triggering cellular responses. The complexity of Ca2+ signals produced by stimulated cells has been revealed by studies in which highly effective techniques have been used to detect Ca2+ ions in the cytosol, such as bioluminescent proteins, fluorescent indicators or ionic currents sensitive to Ca2+. It appears that variations in [Ca2+]i induced by stimulation consist of oscillations of which the frequency, but not the amplitude, depends on the concentration of the hormone. Moreover, by summing the images picked up with a video recorder, it has been possible to demonstrate the changes in [Ca2+]i at the subcellular level and the waves of Ca2+ in stimulated cells.