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

Abstract

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 β-arrestin mobilization and endosomal sorting. The β -arrestin-dependent trafficking of the sst2A somatostatin receptor resembled that of a class B receptor in that upon receptor activation, β-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 β-arrestin mobilization of the sst3 and the sst5 somatostatin receptors resembled that of a class A receptor in that upon receptor activation, β-arrestin and the receptor formed relatively unstable complexes that dissociated at or near the plasma membrane. Consequently, β-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 β-arrestin recruitment. Together, these findings may provide important clues about the regulation of receptor responsiveness during long-term administration of somatostatin analogs.