Abstract
Stable somatostatin analogs (SSAs) are the first choice for medical treatment of pituitary adenomas and other neuroendocrine tumors. The somatostatin analogs octreotide, pasireotide, and veldoreotide primarily have been characterized according to their binding profiles. However, their ability to activate individual somatostatin receptor subtypes (SSTs) has not been directly assessed so far. In this study, we assessed G-protein signaling in human embryonic kidney (HEK293) cells stably expressing G protein-coupled inwardly rectifying potassium (GIRK) channels and SSTs using a novel fluorescence-based membrane potential assay. Dose-response curves obtained for veldoreotide revealed high potency and efficacy in cells expressing SST2, SST4, and SST5. Veldoreotide also inhibited proliferation and chromogranin A secretion in SST4-transfected BON-1 cells. In addition, we assessed G-protein signaling in primary pituitary cultures from SST2 and SST5 knockout mice. Our results show that octreotide mediates its effects selectively via the SST2 receptor. Conversely, pasireotide mediates its effects selectively via the SST5 receptor. In contrast, veldoreotide can activate both SST2 and SST5 receptors under otherwise identical conditions. Thus, veldoreotide is a unique SSA with full agonistic activity at the SST2, SST4, and SST5 receptors.
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