Abstract
Somatostatin, also known as somatotropin-release inhibitory factor, is a cyclopeptide that exerts potent inhibitory actions on hormone secretion and neuronal excitability. Its physiologic functions are mediated by five G protein–coupled receptors (GPCRs) called somatostatin receptor (SST)1–5. These five receptors share common structural features and signaling mechanisms but differ in their cellular and subcellular localization and mode of regulation. SST2 and SST5 receptors have evolved as primary targets for pharmacological treatment of pituitary adenomas and neuroendocrine tumors. In addition, SST2 is a prototypical GPCR for the development of peptide-based radiopharmaceuticals for diagnostic and therapeutic interventions. This review article summarizes findings published in the last 25 years on the physiology, pharmacology, and clinical applications related to SSTs. We also discuss potential future developments and propose a new nomenclature.
Highlights
Introduction and Historical PerspectiveSince their discovery, research on somatostatin and its receptors has remained active with more than 700 papers published annually
Given that only two somatotropin release-inhibiting factor (SRIF) tissue binding sites could be identified using ligands available at that time, the subsequent discovery of five different somatostatin receptor (SST) was surprising and triggered in-depth research into binding properties, localization, and regulation of the ligand. This led to classification of the clinically used SRIF analogs octreotide and lanreotide as SST2-prefering ligands, which in turn stimulated the search for novel compounds that bind either more broadly or more selectively to individual SSTs
These results suggest that the SST2 belongs to the class B G protein–coupled receptor (GPCR) subgroup, because its activation results in robust recruitment of both b-arrestin-1 and -2 (Oakley et al, 2000)
Summary
Research on somatostatin and its receptors has remained active with more than 700 papers published annually. Given that only two SRIF tissue binding sites could be identified using ligands available at that time, the subsequent discovery of five different SSTs was surprising and triggered in-depth research into binding properties, localization, and regulation of the ligand This led to classification of the clinically used SRIF analogs octreotide and lanreotide as SST2-prefering ligands, which in turn stimulated the search for novel compounds that bind either more broadly or more selectively to individual SSTs. In 1996, a structurally related neuropeptide termed cortistatin (CST) with a more restricted distribution in the cerebral cortex and hippocampus was identified (de Lecea et al, 1996). In the past few years, orally available and subtype-selective SST agonists and antagonists have been synthesized Some of these substances may become lead compounds for potential new therapeutic indications directed toward individual SSTs (He et al, 2014; Hirose et al, 2017)
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