ABSTRACT
Somatostatin (SST) is a cyclic neuropeptide that has diverse biological functions, the most important of which are neurotransmitter, antisecretory, and antiproliferative (1). SST-producing cells have been identified at high densities in a variety of normal human tissues, including endocrine, pancreas, gut, thyroid, adrenals, central and peripheral nervous systems, kidneys, prostate, placenta, and submandibular gland (1). Like many other protein hormones, SST is
synthesized as a propeptide, which undergoes tissue-specific processing to produce one of two isoforms, somatostatin-14 (SST-14) or somatostatin-28 (SST-28). The biological effects of SST peptides are mediated by high affinity membrane receptors (SSTRs), all of which bind SST-14 and SST-28 with nanomolar activity. SSTRs have a broad expression pattern and the individual receptors have both overlapping and tissue-specific patterns of expression, with SSTR2 usually being the most widely expressed subtype (1,2). There is a very high degree of amino acid homology among members of the SSTR family (overall approximately 50% amino acid homology) (1). The sequence differences, which reside primarily in the intracellular and extracellular domains, are responsible for their distinct signaling properties. SSTRs elicit their cellular responses through G-protein-linked modulation of various second-messenger systems including adenylyl cyclase, Ca2þ and Kþ ion channels, Naþ=Hþ antiporter, guanylate cyclase, phospholipase C, phospholipase A2, mitogen-activated protein (MAP) kinase and serine, threonine, and phosphotyrosyl protein phosphatase (1). Second messengers used by any SSTR are often cell, tissue, and species specific. The net result of activation of one or more of those signaling mechanisms, in any given tissue, is down-regulation of many synthetic and secretory processes including secretion of growth factors, cellular proliferation, and differentiation (1). Cloning of the five known receptor subtypes resulted in the development of highly specific agonists such as octreotide and lantreotide (SSTR-2 agonists).
