Cellular signaling by endothelin peptides

Endothelins (ET) are potent regulatory peptides that evoke diverse responses in glomerular mesangial cells. These include short-term actions, such as contraction and secretion, and long-term, adaptive responses, such as cell growth. Although much attention has been focused on the second messenger cascades, which govern short-term effects, the pathways of cytosolic and nuclear signaling, which effect long-term changes, remain unclear. Several distal signaling events by ET receptors have been characterized in rat mesangial cells. These include activation of a cytosolic protein kinase, mitogen-activated protein kinase and an inducible transcription factor, activator protein-1 (AP-1). This review focuses on the activation of mitogen-activated protein kinase and activator protein-1 by ET and discusses the potential role of these third and fourth messengers in controlling long-term cellular adaptations. Characterization of these and other cytosolic and nuclear signals should provide important insights into the pleiotropic actions of ET peptides.