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

The physiological responses of somatostatin are mediated by five different G protein-coupled receptors. Although agonist-induced endocytosis of the various somatostatin receptor subtypes (sst1–sst5) has been studied in detail, little is known about their postendocytic trafficking. Here we show that somatostatin receptors profoundly differ in patterns of -arrestin mobilization and endosomal sorting. The -arrestin-dependent trafficking of the sst2A somatostatin receptor resembled that of a class B receptor in that upon receptor activation, -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 sst2A receptor. Unlike other class B receptors, however, the sst2A receptor was rapidly resensitized and recycled to the plasma membrane. The -arrestin mobilization of the sst3 and the sst5 somatostatin receptors resembled that of a class A receptor in that upon receptor activation, -arrestin and the receptor formed relatively unstable complexes that dissociated at or near the plasma membrane. Consequently, -arrestin was excluded from sst3-containing vesicles. Unlike other class A receptors, a large proportion of sst3 receptors was subject to ubiquitin-dependent lysosomal degradation and did not rapidly recycle to the plasma membrane. The sst4 somatostatin receptor is unique in that it did not exhibit agonist-dependent receptor phosphorylation and -arrestin recruitment. Together, these findings may provide important clues about the regulation of receptor responsiveness during long-term administration of somatostatin analogs