Somatostatin is a tetradecapeptide that is widely distributed in the body. It acts on multiple organs including brain, pituitary, gut, exocrine and endocrine pancreas, adrenals, thyroid, and kidneys to inhibit release of many hormones and other secretory proteins. In addition, it functions as a neuropeptide affecting the electrical activity of neurons. Somatostatin exerts its biological effects by binding to specific high-affinity receptors, which appear in many cases to be coupled to GTP-binding proteins. Here we report the cloning, functional expression, and tissue distribution of two different somatostatin receptors (SSTRs). SSTR1 and SSTR2 contain 391 and 369 amino acids, respectively, and are members of the superfamily of receptors having seven transmembrane segments. There is 46% identity and 70% similarity between the amino acid sequences of SSTR1 and SSTR2. Stably transfected Chinese hamster ovary cells expressing SSTR1 or SSTR2 exhibit specific somatostatin binding, with an apparently higher afflnity for somatostatin-14 than somatostatin-28, an NH2-terminally extended form of somatostatin-14. RNA blotting studies show that SSTR1 and SSTR2 are expressed at highest levels in jejunum and stomach and in cerebrum and kidney, respectively. A SSTR1 probe hybridized to multiple DNA fragments in EcoRI digests of human and mouse DNA, indicating that SSTR1 and SSTR2 are members of a larger family of somatostatin receptors. Thus, the biological effects of somatostatin are mediated by a family of receptors that are expressed in a tissue-specific manner.Somatostatin is a tetradecapeptide that was first isolated from hypothalamic extracts and shown to be a potent inhibitor of growth hormone secretion from the anterior pituitary (1). Subsequent studies have shown that it is widely distributed occurring in the central nervous system and peripheral tissues such as stomach, intestine, and pancreas (2). Somatostatin has diverse physiological effects that are tissue-specific (2). It can function as a neurotransmitter as well as a hormone. Its hormonal effects include suppression of release of many pituitary, pancreatic, and gastrointestinal hormones and other secretory proteins.Somatostatin-14 is a member ofa family of somatostatin-like peptides that also includes an NH2-terminally extended form, somatostatin-28 (3, 4). The two principal bioactive forms of somatostatin, somatostatin-14 and -28, are derived by tissuespecific proteolytic processing of prosomatostatin, the 92-amino acid precursor of somatostatin-14 and -28 (5) and are present at various concentrations in different tissues. Although somatostatin-14 and -28 may have common effects on target tissues, they show different potencies, suggesting that their actions are mediated by different receptors (2). For example, somatostatin-14 appears to be relatively more selective for inhibition of glucagon and gastric acid secretion, whereas somatostatin-28 is a more specific inhibitor of growth hormone, insulin, and pancreatic exocrine secreziin (6).Somatostatin-14 ...