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 (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.
Institut für Pharmakologie und Toxikologie, Otto-von-Guericke-Universität, Leipziger Strasse 44, 39120 Magdeburg, Germany.
Giovanni
G
Tulipano
Ralf
R
Stumm
Manuela
M
Pfeiffer
Hans-Jürgen
HJ
Kreienkamp
Volker
V
Höllt
Stefan
S
Schulz
D000595:Amino Acid Sequence; D000818:Animals; D019390:Arrestins / Q000737:chemistry / Q000235:genetics / Q000502:physiology*; D002460:Cell Line; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism*; D011992:Endosomes / Q000502:physiology*; D054769:G-Protein-Coupled Receptor Kinase 2; D054770:G-Protein-Coupled Receptor Kinase 3; D006801:Humans; D007668:Kidney; D051379:Mice; D008969:Molecular Sequence Data; D010766:Phosphorylation; D011817:Rabbits; D051381:Rats; D017481:Receptors, Somatostatin / Q000502:physiology*; D016415:Sequence Alignment; D017386:Sequence Homology, Amino Acid; D051552:beta-Adrenergic Receptor Kinases; D000071557:beta-Arrestins
D019390:Arrestins; D017481:Receptors, Somatostatin; D000071557:beta-Arrestins; D017868:Cyclic AMP-Dependent Protein Kinases; D054770:G-Protein-Coupled Receptor Kinase 3; C517848:GRK3 protein, human; C517850:GRK3 protein, mouse; C496569:Grk2 protein, rat; C517851:Grk3 protein, rat; D051552:beta-Adrenergic Receptor Kinases; D054769:G-Protein-Coupled Receptor Kinase 2