Role of cytoplasmic tail of the type 1A angiotensin II receptor in agonist- and phorbol ester-induced desensitization

Circulation Research
H TangT Inagami

Abstract

To investigate mechanisms underlying the agonist-induced desensitization of the type 1A angiotensin II receptor (AT1A-R), we have stably expressed in Chinese hamster ovary (CHO) cells the wild-type receptor and truncated mutants lacking varying lengths of the cytoplasmic tail. Assay of inositol 1,4,5-trisphosphate (IP3) formation in response to agonist demonstrated that the truncated mutants T318, T328, and T348 lacking the last 42, 32, or 12 amino acid residues, respectively, couple with Gq protein with an efficiency similar to that of full-length receptors, whereas coupling of Gq protein was abolished in the T310 truncated mutant devoid of the carboxyl-terminal 50 amino acids. Exposure of CHO/AT1A-R cells expressing the wild-type AT1A-R to angiotensin II resulted in rapid and dose-dependent homologous desensitization of receptor-mediated IP3 formation, which was independent of the receptor internalization. Mastoparan, an activator of G protein-coupled receptor kinase (GRK), induced desensitization of the AT1A-R. The agonist-induced desensitization of the receptor was largely prevented by heparin, a potent inhibitor of GRK, whereas it was only partially attenuated by a protein kinase C (PKC)-specific inhibitor. The homologous ...Continue Reading

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