Signalling pathways activated by endothelin stimulation of renal cells

1. Endothelin mediates its effects in a variety of renal cells via a multiplicity of intracellular signalling pathways. 2. Stimulation of phosphatidylinositol-specific phospholipase C (PI-PLC), resulting in the activation of inositol trisphosphate and diacylglycerol, can be detected even at picomolar concentrations of peptide. 3. Endothelin activation of cPLA(2) is sensitive to ambient [Ca2+](i), is not contingent upon protein kinase C activation and is independent of PI-PLC stimulation, being coupled to the endothelin receptor in a yet to be determined manner. 4. Activation by endothelin of phosphatidylcholine-specific phospholipase D is under the dual regulation of protein kinase C and [Ca2+](i), with protein kinase C being the major regulator and [Ca2+](i) playing a secondary, modulatory role. 5. Phosphatidylcholine-specific phospholipase C (PC-PLC) is stimulated by endothelin and accounts for the prolonged activation of diacylglycerol by this peptide. PC-PLC activity is critically dependent upon [Ca2+](i), whereas protein kinase C plays no role in modulating the activity of this enzyme. 6. Endothelin enhances the phosphorylation of protein tyrosine kinases, with evidence that phosphorylation of pp(60) Src may be an important early event.