Agonist-biased signaling at the sst2A receptor: the multi-somatostatin analogs KE108 and SOM230 activate and antagonize distinct signaling pathways

Cescato, Renzo; Loesch, Kimberly A; Waser, Beatrice; Mäcke, Helmut R; Rivier, Jean E; Reubi, Jean Claude; Schonbrunn, Agnes (2010). Agonist-biased signaling at the sst2A receptor: the multi-somatostatin analogs KE108 and SOM230 activate and antagonize distinct signaling pathways. Molecular endocrinology, 24(1), pp. 240-9. Bethesda, Md.: Endocrine Society 10.1210/me.2009-0321

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Somatostatin analogs that activate the somatostatin subtype 2A (sst2A) receptor are used to treat neuroendocrine cancers because they inhibit tumor secretion and growth. Recently, new analogs capable of activating multiple somatostatin receptor subtypes have been developed to increase tumor responsiveness. We tested two such multi-somatostatin analogs for functional selectivity at the sst2A receptor: SOM230, which activates sst1, sst2, sst3, and sst5 receptors, and KE108, which activates all sst receptor subtypes. Both compounds are reported to act as full agonists at their target sst receptors. In sst2A-expressing HEK293 cells, somatostatin inhibited cAMP production, stimulated intracellular calcium accumulation, and increased ERK phosphorylation. SOM230 and KE108 were also potent inhibitors of cAMP accumulation, as expected. However, they antagonized somatostatin stimulation of intracellular calcium and behaved as partial agonists/antagonists for ERK phosphorylation. In pancreatic AR42J cells, which express sst2A receptors endogenously, SOM230 and KE108 were both full agonists for cAMP inhibition. However, although somatostatin increased intracellular calcium and ERK phosphorylation, SOM230 and KE108 again antagonized these effects. Distinct mechanisms were involved in sst2A receptor signaling in AR42J cells; pertussis toxin pretreatment blocked somatostatin inhibition of cAMP accumulation but not the stimulation of intracellular calcium and ERK phosphorylation. Our results demonstrate that SOM230 and KE108 behave as agonists for inhibition of adenylyl cyclase but antagonize somatostatin's actions on intracellular calcium and ERK phosphorylation. Thus, SOM230 and KE108 are not somatostatin mimics, and their functional selectivity at sst2A receptors must be considered in clinical applications where it may have important consequences for therapy.

Item Type:

Journal Article (Original Article)

Division/Institute:

04 Faculty of Medicine > Service Sector > Institute of Pathology

UniBE Contributor:

Cescato, Renzo; Waser, Beatrice and Reubi, Jean-Claude

ISSN:

0888-8809

Publisher:

Endocrine Society

Language:

English

Submitter:

Factscience Import

Date Deposited:

04 Oct 2013 14:08

Last Modified:

04 May 2014 23:04

Publisher DOI:

10.1210/me.2009-0321

PubMed ID:

19910453

Web of Science ID:

000273071800020

URI:

https://boris.unibe.ch/id/eprint/712 (FactScience: 200446)

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