Phosphorylation of four amino acid residues in the carboxyl terminus of the rat somatostatin receptor subtype 3 is crucial for its desensitization and internalization

Roth, A.; Kreienkamp, H.J.; Meyerhof, W.; Richter, D.

Journal of Biological Chemistry 272(38): 23769-23774


ISSN/ISBN: 0021-9258
PMID: 9295322
DOI: 10.1074/jbc.272.38.23769
Accession: 009189106

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Agonist-dependent internalization of the rat somatostatin receptor subtype 3 (SSTR3) requires four hydroxyl amino acids (Ser-341, Ser-346, Ser-351, and Thr-357) in the receptor C terminus (Roth, A., Kreienkamp, H.-J., Nehring, R., Roostermann, D., Meyerhof, W. and Richter, D. (1997) DNA Cell Biol. 16, 111-119). Here we report on the molecular mechanism responsible for the endocytotic process by analyzing the agonist-dependent phosphorylation of wild-type and mutant receptors expressed in human embryonic kidney cells. Wild-type SSTR3 is phosphorylated in response to agonist treatment. Phosphorylation is markedly reduced in a S341A/S346A/S351A triple mutant and is also reduced, but to a lesser extent, in the T357A point mutant. Internalization of the wild-type receptor is preceded by a functional desensitization of the receptor; in contrast, the triple serine mutant does not desensitize after treatment with agonists as assayed by its ability to inhibit forskolin-stimulated adenylate cyclase activity. After internalization via a clathrin-coated vesicle mediated endocytotic pathway, SSTR3 efficiently recycles to the cell surface, suggesting that agonist mediated endocytosis is necessary for the functional resensitization of a phosphorylated and desensitized receptor.