Differential beta-arrestin trafficking and endosomal sorting of somatostatin receptor subtypes

• Published in: The Journal of biological chemistry Vol. 279; no. 20; pp. 21374 - 21382
• Main Authors: Tulipano, Giovanni, Stumm, Ralf, Pfeiffer, Manuela, Kreienkamp, Hans-Jürgen, Höllt, Volker, Schulz, Stefan
• Format: Journal Article
• Language: English
• Published: United States 14.05.2004
• Subjects: Amino Acid Sequence; Animals; Arrestins - chemistry; Arrestins - genetics; Arrestins - physiology; beta-Adrenergic Receptor Kinases; beta-Arrestins; Cell Line; Cyclic AMP-Dependent Protein Kinases - metabolism; Endosomes - physiology; G-Protein-Coupled Receptor Kinase 2; G-Protein-Coupled Receptor Kinase 3; Humans; Kidney; Mice; Molecular Sequence Data; Phosphorylation; Rabbits; Rats; Receptors, Somatostatin - physiology; Sequence Alignment; Sequence Homology, Amino Acid
• ISSN: 0021-9258
• DOI: 10.1074/jbc.M313522200

The physiological responses of somatostatin are mediated by five different G protein-coupled receptors. Although agonist-induced endocytosis of the various somatostatin receptor subtypes (sst(1)-sst(5)) has been studied in detail, little is known about their postendocytic trafficking. Here we show that somatostatin receptors profoundly differ in patterns of beta-arrestin mobilization and endosomal sorting. The beta-arrestin-dependent trafficking of the sst(2A) somatostatin receptor resembled that of a class B receptor in that upon receptor activation, beta-arrestin and the receptor formed stable complexes and internalized together into the same endocytic vesicles. This pattern was dependent on GRK2 (G protein-coupled receptor kinase 2)-mediated phosphorylation of a cluster of phosphate acceptor sites within the cytoplasmic tail of the sst(2A) receptor. Unlike other class B receptors, however, the sst(2A) receptor was rapidly resensitized and recycled to the plasma membrane. The beta-arrestin mobilization of the sst(3) and the sst(5) somatostatin receptors resembled that of a class A receptor in that upon receptor activation, beta-arrestin and the receptor formed relatively unstable complexes that dissociated at or near the plasma membrane. Consequently, beta-arrestin was excluded from sst(3)-containing vesicles. Unlike other class A receptors, a large proportion of sst(3) receptors was subject to ubiquitin-dependent lysosomal degradation and did not rapidly recycle to the plasma membrane. The sst(4) somatostatin receptor is unique in that it did not exhibit agonist-dependent receptor phosphorylation and beta-arrestin recruitment. Together, these findings may provide important clues about the regulation of receptor responsiveness during long-term administration of somatostatin analogs.