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J. Biol. Chem., Vol. 280, Issue 25, 24011-24021, June 24, 2005

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Somatostatin Receptor Type 5 Modulates Somatostatin Receptor Type 2 Regulation of Adrenocorticotropin Secretion^*

Anat Ben-Shlomo, Kolja A. Wawrowsky, Irina Proekt, Nathaniel M. Wolkenfeld, Song-Guang Ren, John Taylor, Michael D. Culler, and Shlomo Melmed¶

From the Department of Medicine, Cedars Sinai Research Institute, David Geffen School of Medicine, UCLA, Los Angeles, California 90048 and Biomeasure Inc., Milford, Massachusetts 01757

Somatostatin inhibits adrenocorticotropin (ACTH) secretion from pituitary tumor cells. To assess the contribution of somatostatin receptor subtype 5 (SST5) to somatostatin receptor subtype 2 (SST2) action in these cells, we assessed multipathway responses to novel highly monoreceptor-selective peptide agonists and multireceptor agonists, including octreotide and somatostatin-28. Octreotide and somatostatin-28 cell membrane binding affinities correlated with their respective SST2-selective peptide ligand. Although octreotide had similar inhibiting potency (picomolar) for cAMP accumulation and ACTH secretion as an SST2-selective agonist, somatostatin-28 exhibited a higher potency (femtomolar). Baseline spontaneous calcium oscillations assessed by fluorescent confocal microscopy revealed two distinct effects: SST2 activation reduced oscillations at femtomolar concentrations reflected by high inhibiting potency of averaged normalized oscillation amplitude, whereas SST5 activation induces brief oscillation pauses and increased oscillation amplitude. Octreotide exhibits an integrated effect of both receptors; however, somatostatin-28 exhibited a complex response with two separate inhibitory potencies. SST2 internalization was visualized with SST2-selective agonist at lower concentrations than for octreotide or somatostatin-28, whereas SST5 did not internalize. Using monoreceptor-selective peptide agonists, the results indicate that, in AtT-20 cells, SST5 regulates the dominant SST2 action, attenuating SST2 effects on intracellular calcium oscillation and internalization. This may explain superior somatostatin-28 potency and provides a rationale for somatostatin ligand design to treat ACTH-secreting pituitary tumors.

Received for publication, February 22, 2005 , and in revised form, April 22, 2005.

^* The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

^¶ To whom correspondence should be addressed: Cedars-Sinai Medical Center, 8700 Beverly Blvd., Academic affairs, Rm. 2015, Los Angeles, CA 90048. Tel.: 310-423-4691; Fax: 310-423-0119, E-mail: Melmed{at}csmc.edu.

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