Citation

4165 total record number 127 records this year

Vasopressin receptor 2 mutations in the nephrogenic syndrome of inappropriate antidiuresis show different mechanisms of constitutive activation for G protein coupled receptors

Vezzi, V;Ambrosio, C;Gr, MC;Molinari, P;Sral, G;Costa, T;Onaran, HO;Cotecchia, S;

Vasopressin receptor 2 (V2R) mutations causing the nephrogenic syndrome of inappropriate antidiuresis (NSIAD) can generate two constitutively active receptor phenotypes. One type results from residue substitutions in several V2R domains and is sensitive to vaptan inverse agonists. The other is only caused by Arg 137 replacements and is vaptan resistant. We compared constitutive and agonistdriven interactions of the vaptan-sensitive F229V and vaptan-resistant R137C/L V2R mutations with β-arrestin 1, β-arrestin 2, and Gαs, using null fbroblasts reconstituted with individual versions of the ablated transduction protein genes. F229V displayed very high level of constitutive activation for Gs but not for β-arrestins, and enhanced or normal responsiveness to agonists and inverse agonists. In contrast, R137C/L mutants exhibited maximal levels of constitutive activation for βarrestin 2 and Gs, minimal levels for β-arrestin 1, but a sharp decline of ligands sensitivity at all transducer interactions. The enhanced constitutive activity and reduced ligand sensitivity of R137 mutants on cAMP signaling persisted in cells lacking β-arrestins, indicating that these are intrinsic molecular properties of the mutations, not the consequence of altered receptor trafcking. The results suggest that the two group of NSIAD mutations represent two distinct molecular mechanisms of constitutive activation in GPCRs.