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Coexpression of Somatostatin Receptor Subtype 5 Affects Internalization and Trafficking of Somatostatin Receptor Subtype 2

Department of Neurology and Neurosurgery (N.S., L.G., J.W., P.S., A.B., T.S.), McGill University, and the Montreal Neurological Institute, Montréal, Québec, Canada H3A 2B4; and Institut de Pharmacologie Moléculaire et Cellulaire (J.M.), Unité Mixte de Recherche 6097, Université de Nice-Sophia Antipolis, 06560 Valbonne, France

Address all correspondence and requests for reprints to: Thomas Stroh, Ph.D., Montreal Neurological Institute, McGill University, 3801 University Street, Montréal, Québec, Canada H3A 2B6. E-mail: thomas.stroh{at}mcgill.ca.

The somatostatin [somatotropin release-inhibiting factor (SRIF)] receptor subtypes sst_2A and sst₅ are frequently coexpressed in SRIF-responsive cells, including endocrine pituitary cells. We previously demonstrated that sst_2A and sst₅ exhibit different subcellular localizations and regulation of cell surface expression, although they have similar signaling properties. We investigated here whether sst_2A and sst₅ functionally interact in cells coexpressing the two receptor subtypes. We stimulated both transfected cells stably expressing sst_2A alone (CHO-sst_2A) or together with sst₅ (CHO-sst_2A+5) and the pituitary cell line AtT20, which endogenously expresses the two receptor subtypes, with either the nonselective agonist [D-Trp⁸]-SRIF-14 or the sst₂-selective agonist L-779,976. In CHO-sst_2A cells, stimulation with either ligand resulted in the loss of approximately 75% of cell surface SRIF binding sites and massive internalization of sst_2A receptors. The cells were desensitized to subsequent stimulation with [D-Trp⁸]-SRIF-14, which failed to inhibit forskolin-evoked cAMP accumulation. Similarly, in CHO-sst_2A+5 and AtT20 cells, [D-Trp⁸]-SRIF-14 induced the loss of 60–70% of SRIF binding sites as well as massive sst_2A endocytosis. By contrast, in cells expressing both sst_2A and sst₅, selective stimulation of sst_2A with L-779,976 resulted in only 20–40% loss of cell surface binding and markedly reduced sst_2A internalization. Consequently, whereas CHO-sst_2A+5 and AtT20 cells stimulated with [D-Trp⁸]-SRIF-14 were desensitized to a second stimulation with the same agonist, cells prestimulated with L-779,976 were not desensitized to subsequent [D-Trp⁸]-SRIF-14 stimulation. These findings indicate that the presence of sst₅ in the same cells modulates trafficking and cell surface regulation of sst_2A and cellular desensitization to the effects of SRIF.