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Homologous and Heterologous Regulation of Somatostatin Receptor 2

Department of Integrative Biology and Pharmacology, University of Texas Health Sciences Center Houston, Houston, Texas 77225

Address all correspondence and requests for reprints to: Agnes Schonbrunn, Department of Integrative Biology and Pharmacology, University of Texas-Houston, P. O. Box 20708, Houston, Texas 77225. E-mail: Agnes.Schonbrunn{at}uth.tmc.edu.

We previously demonstrated that phosphorylation of somatostatin receptor 2A (sst2A) is rapidly increased in transfected cells both by agonist and by the protein kinase C (PKC) activator phorbol myristate acetate (PMA). Here, we investigate whether PKC-mediated receptor phosphorylation is involved in the homologous or heterologous regulation of endogenous sst2 receptors in AR42J pancreatic acinar cells upon stimulation by agonist or by cholecystokinin (CCK) or bombesin (BBS). Somatostatin, PMA, CCK, and BBS all increased sst2A receptor phosphorylation 5- to 10-fold within minutes. Somatostatin binding also caused rapid internalization of the ligand-receptor complex, and PMA, CCK, and BBS all stimulated this internalization further. Additionally, sst2 receptor-mediated inhibition of adenylyl cyclase was desensitized by all treatments. Somatostatin, as well as peptidic (SMS201–995) and nonpeptidic (L-779,976) sst2 receptor agonists increased the EC₅₀ for somatostatin inhibition 20-fold. In contrast, pretreatment with BBS, CCK, or PMA caused a modest 2-fold increase in the EC₅₀ for cyclase inhibition. Whereas the PKC inhibitor GF109203X abolished sst2A receptor phosphorylation by CCK, BBS, and PMA, it did not alter the effect of somatostatin, demonstrating that these reactions were catalyzed by different kinases. Consistent with a functional role for PKC-mediated receptor phosphorylation, GF109203X prevented PMA stimulation of sst2 receptor internalization. Surprisingly, however, GF109203X did not inhibit BBS and CCK stimulation of sst2A receptor endocytosis. These results demonstrate that homologous and heterologous hormones induce sst2A receptor phosphorylation by PKC-independent and -dependent mechanisms, respectively, and produce distinct effects on receptor signaling and internalization. In addition, the heterologous hormones also modulate sst2 receptor internalization by a novel mechanism that is independent of receptor phosphorylation.

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