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Differential Effects of Octreotide and Pasireotide on Somatostatin Receptor Internalization and Trafficking in Vitro

Department of Pharmacology and Toxicology (S.L., D.L.), Otto-von-Guericke-University, D-39120 Magdeburg, Germany; Department of Pharmacology (F.N.), Julius-Maximilians-University, D-97078 Würzburg, Germany; Novartis Institutes for Biomedical Research (H.A.S.), CH-4057 Basel, Switzerland; and Department of Pharmacology and Toxicology (F.N., S.S.), Friedrich-Schiller-University, D-07743 Jena, Germany

Address all correspondence and requests for reprints to: Stefan Schulz, Department of Pharmacology and Toxicology, Friedrich-Schiller-University, Nonnenplan 4, 07743 Jena, Nonnenplan 4, Germany. E-mail: Stefan.Schulz{at}mti.uni-jena.de.

Objective: The clinically used somatostatin analogs, octreotide and lanreotide, act primarily by binding to somatostatin receptor 2 (sst₂). In contrast, the novel multireceptor ligand pasireotide (SOM230) binds with high affinity to somatostatin receptor subtypes sst₁, sst₂, sst₃, and sst₅. SOM230 is currently under clinical evaluation for treatment of acromegaly, Cushing’s disease, and octreotide-resistant carcinoid tumors. However, the effects of SOM230 on internalization and postendosomal sorting of individual human somatostatin receptor subtypes have not been determined so far.

Results: Here we show that SOM230 was less potent than octreotide in inducing internalization and signaling of sst₂ receptors expressed in human embryonic kidney cells. In contrast, SOM230 was more potent than octreotide in inducing internalization and signaling of sst₃ and sst₅ receptors. Both SOM230 and octreotide stimulated a rapid down-regulation of sst₃ but not of sst₂ or sst₅ receptors. SOM230 and octreotide profoundly differed in their patterns of sst₂-stimulated β-arrestin mobilization. Whereas octreotide-mediated receptor activation led to the formation of stable complexes facilitating the internalization of sst₂ and β-arrestin-2 into the same endocytic vesicles, SOM230-mediated receptor activation led to the formation of unstable complexes that dissociated at or near the plasma membrane. Consequently, sst₂ receptors recycled rapidly to the plasma membrane after endocytosis in SOM230-treated cells, but not in octreotide-treated cells.

Conclusion: We show that SOM230 modulates somatostatin receptor trafficking in a manner clearly distinct from octreotide and somatostatin. These findings may provide an explanation for the differential regulation of somatostatin receptor responsiveness during long-term administration of stable somatostatin analogs.

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