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Cell Growth Inhibition and Functioning of Human Somatostatin Receptor Type 2 Are Modulated by Receptor Heterodimerization

Fraser Laboratories For Diabetes Research (M.G., H.A., U.K.), Department of Medicine, Royal Victoria Hospital, Montreal, Quebec, Canada H3A 1A1; Department of Pharmacology and Therapeutics (M.G., B.C.), McGill University, Montreal, Quebec, Canada H3A 2K6; Faculty of Medicine (P.J.), Centre Hospitalier Universitaire Timone, 13385 Marseille, France; and Faculty of Pharmaceutical Sciences (U.K.), Division of Pharmacology and Toxicology, University of British Columbia, Vancouver, Canada V6T 1RZ

Address all correspondence and requests for reprints to: Dr. Ujendra Kumar, Faculty of Pharmaceutical Sciences, Division of Pharmacology and Toxicology, The University of British Columbia, 2146 East Mall, Vancouver, Canada V6T 1RZ. E-mail: ujkumar{at}interchange.ubc.ca.

Somatostatin (SST) analogs have been successfully used in the medical treatment of acromegaly, caused by GH hypersecreting pituitary adenomas. Patients on SST analogs rarely develop tachyphylaxis despite years of continuous administration. It has been recently proposed that a functional association between SST receptor (SSTR) subtypes 2 and 5 exists to account for this behavior; however, a physical interaction has yet to be identified. Using both coimmunoprecipitation and photobleaching fluorescence resonance energy transfer microscopy techniques, we determined that SSTR2 and SSTR5 heterodimerize. Surprisingly, selective activation of SSTR2 and not SSTR5, or their costimulation, modulates the association. The SSTR2-selective agonist L-779,976 is more efficacious at inhibiting adenylate cyclase, activating ERK1/2, and inducing the cyclin-dependent kinase inhibitor p27^Kip1 in cells expressing both SSTR2 and SSTR5 compared with SSTR2 alone. Furthermore, cell growth inhibition by L-779,976 treatment was markedly extended in coexpressing cells. Trafficking of SSTR2 is also affected upon heterodimerization, an attribute corresponding to modifications in β-arrestin association kinetics. Activation of SSTR2 results in the recruitment and stable association of β-arrestin, followed by receptor internalization and intracellular receptor pooling. In contrast, heterodimerization increases the recycling rate of internalized SSTR2 by destabilizing its interaction with β-arrestin. Given that SST analogs show preferential binding to SSTR2, these data provide a mechanism for their effectiveness in controlling pituitary tumors and the absence of tolerance seen in patients undergoing long-term administration.