LIGAND-INDUCED CLEAVAGE OF THE V-2 VASOPRESSIN RECEPTOR BY A PLASMA-MEMBRANE METALLOPROTEINASE

The proteolytic cleavage of a G protein-coupled peptide hormone recept or, the renal V-2 vasopressin receptor, by a plasma membrane proteinas e was investigated. In the absence of protease inhibitors during incub ation of bovine kidney membranes with a photoreactive vasopressin agon ist, V-2 receptor truncation leads to a labeled receptor fragment with M(r) 30,000. The V-2 receptor-degrading enzyme could be completely in hibited by zinc ions yielding the native V-2 receptor glycoprotein wit h M(r) 58,000. Studies with inhibitors of metalloendopeptidases involv ed in peptide hormone metabolism and with peptide substrates spanning the V-2 receptor cleavage site classify the receptor protease as metal loendoproteinase with specificity for longer substrates. Comparison of the NH2-terminal protein sequence of the truncated M(r) 30,000 V-2 re ceptor with the sequence deduced from the cDNA of the cloned bovine V- 2 receptor shows that cleavage occurs between Gln(92) and Val(93) of t he second transmembrane helix close to an extracellular agonist bindin g site. V-2 receptor proteolysis was dependent on the presence of a ho rmonal ligand. It occurred rapidly after hormone binding and led to a loss of ligand binding properties of the truncated V-2 receptor. The d ata suggest that the endogenous V-2 receptor-degrading metalloendoprot einase regulates V-2 receptor function. The novel pathway may contribu te to the termination of signal transmission.