Vascular biology of endothelin signal transduction.

1. Endothelins regulate cell function by interacting with two classes of cell surface receptors, ETA and ETB receptors. Both receptor types are members of the heptahelical transmembrane-spanning receptor superfamily and couple via G-proteins to multiple intracellular effectors. 2. Many of the cellular responses induced by endothelins are mediated by changes in cytoplasmic Ca2+ concentration. Stimulation of inositol 1,4,5-trisphosphate (IP3) formation promotes release of Ca2+ from intracellular stores via IP3-sensitive Ca2+ channels. This mechanism accounts for the initial transient peak of the Ca2+ elevation. The entry of Ca2+ across the plasma membrane through multiple types of Ca2+ channels is responsible for the sustained phase of Ca2+ elevation and, together, both mechanisms regulate cell function. 3. Endothelin-mediated Ca2+ signals vary markedly in duration, spatial organization and temporal pattern. The elevations in Ca2+ are sustained, transient or oscillatory and occur either globally or are localized to discrete spatial domains. These different Ca2+ signals, which are dependent on the availability of specific ion channels, control distinct cellular functions. Ryanodine-sensitive Ca2+ release channels may be important in determining the organization of the Ca2+ signal. 4. Endothelin-induced Ca2+ elevations near the plasma membrane stimulate the opening of Ca(2+)-dependent K+ and Cl- channels. These channels are key regulators of membrane potential and, consequently, regulate the activity of voltage-dependent Ca2+ influx pathways. 5. Endothelin regulates the growth and differentiation of cells. It markedly potentiates the mitogenic response of other growth factors, an effect that involves activation of the mitogen-activated protein kinase cascade and induction of early response genes. 6. Finally, the vascular actions of endothelin are influenced by the relative expression of specific ion channels, the spatial and temporal pattern of the Ca2+ signal and the cellular composition of the vascular wall.