DESENSITIZATION OF HUMAN ENDOTHELIN-A RECEPTOR

The response of G-protein-coupled receptors is modulated by homologous desensitization. Because endothelin A receptor (ET(A)) plays a part in vasoconstriction, the extent of desensitization and resensitization of endothelin responsiveness was studied. A cDNA clone encoding human ET(A) receptor was isolated based on similarities to bovine endothelin A receptor. Xenopus laevis oocytes injected with cloned mRNA transcripts were used as a model system for analyzing desensitization. Human neurokinin A (NKA) receptor was used for comparison with ET(A) receptor in desensitization experiments. Xenopus laevis oocytes injected with the two receptor mRNAs show homologous desensitization but variable rates of recovery. Human NKA receptors desensitize within 5 min and resensitize after 20-30 min. Human ET(A) receptors also desensitize within 5 min but have a prolonged resensitization period lasting 1.5-2 h. Such a prolonged recovery period is unique to this class of receptors and may serve to regulate some of the deleterious effects mediated by the ET(A) receptor. The mechanism of differential desensitization is being investigated using genetically engineered mutants of human ET(A) receptor.