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Agonist-Induced Endocytosis of Rat Somatostatin Receptor 1

Department of Dermatology (D.R., M.S.), Interdisziplinäres Zentrum für Klinische Forschung (IZKF) Münster, and Ludwig Boltzmann Institute for Cell and Immunobiology of the Skin, University of Münster, 48149 Münster, Germany; Department of Molecular Genetics (O.J.K., N.B., W.M.), German Institute of Human Nutrition Potsdam-Rehbruecke, 14558 Nuthetal, Germany; and Department of Surgery and Physiology (G.S.C., N.W.B.), University of California, San Francisco, San Francisco, California 94143-0660

Address all correspondence and requests for reprints to: Dr. D. Roosterman, Department of Dermatology and Ludwig Boltzmann Institute for Cell and Immunobiology of the Skin, Von-Esmarch-Str. 58, D-48148 Münster, Germany. E-mail: roosterman{at}gmx.net.

Somatostatin-receptor 1 (sst1) is an autoreceptor in the central nervous system that regulates the release of somatostatin. Sst1 is present intracellularly and at the cell surface. To investigate sst1 trafficking, rat sst1 tagged with epitope was expressed in rat insulinoma cells 1046-38 (RIN-1046-38) and tracked by antibody labeling. Confocal microscopic analysis revealed colocalization of intracellularly localized rat sst1-human simplex virus (HSV) with Rab5a-green fluorescent protein and Rab11a-green fluorescent protein, indicating the distribution of the receptor in endocytotic and recycling organelles. Somatostatin-14 induced internalization of cell surface receptors and reduction of binding sites on the cell surface. It also stimulated recruitment of intracellular sst1-HSV to the plasma membrane. Confocal analysis of sst1-HSV revealed that the receptor was initially transported within superficial vesicles. Prolonged stimulation of the cells with the peptide agonist induced intracellular accumulation of somatostatin-14. Because the number of cell surface binding sites did not change during prolonged stimulation, somatostatin-14 was internalized through a dynamic process of continuous endocytosis, recycling, and recruitment of intracellularly present sst1-HSV. Accumulated somatostatin-14 bypassed degradation via the endosomal-lysosomal route and was instead rapidly released as intact and biologically active somatostatin-14. Our results show for the first time that sst1 mediates a dynamic process of endocytosis, recycling, and reendocytosis of its cognate ligand.

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