Intracellular Ca2+ signalling in secretory cells.
The secretion of ions and fluid plays a critical role in a variety of physiological activities that are vital to homeostatic mechanisms in animals. Control of such secretory activity is achieved by a range of neurotransmitters and hormones many of which act intracellularly by generating the second messenger inositol 1,4,5-trisphosphate (InsP3) and increasing cytosolic free calcium ion concentrations ([Ca2+]i). These increases are achieved by a combination of the InsP3-induced release of Ca2+ from specific intracellular stores and the activation of Ca2+ entry from the extracellular environment. The [Ca2+]i signal represents a balance between the adequate activation of components of the secretory mechanism and the avoidance of [Ca2+]i levels that are toxic to the cell. Resting [Ca2+]i is maintained low by the action of Ca2+ pumps on the intracellular stores and plasma membrane, with the result that gradients for Ca2+ movement into the cytosol from either of these two sources are very large and there is considerable potential for achieving rapid increases in [Ca2+]i. Consequently, for successful Ca2+ signalling, it is imperative that these two mechanisms of raising [Ca2+]i (i.e. Ca2+ release and Ca2+ entry) are closely integrated. Current models emphasize the activation of Ca2+ entry as a downstream result of the emptying of the intracellular stores ("capacitative' model). Whilst this may be true for situations of maximal stimulation, recent experiments on the oscillatory [Ca2+]i responses typical of more physiological levels of stimulation indicate a previously unsuspected, independent activation of Ca2+ entry involving arachidonic acid. This arachidonic-acid-activated entry plays a key role, along with InsP3, in inducing the repetitive release of Ca2+ from the stores to produce the [Ca2+]i oscillations. In this way, the two components responsible for the elevation of [Ca2+]i are intimately related and their dual effects closely coordinated, resulting in the finely tuned control of agonist-induced changes in [Ca2+]i.