A group of new peptide ligands displaying high selectivity for binding to somatostatin receptor subtypes 2, 3 or 5 have been used to characterize somatostatin receptor involvement in the inhibition of glucagon secretion in rats. It was found that NC-8-12 and DC-25-100, which have high affinity for SSTR2 and much less affinity for the type 5 receptor, were by far the most potent inhibitors of glucagon secretion with EC50s of 48 and 18 nmole, respectively, relative to somatostatin itself (EC50 131 nmole). These two analogs were actually much less potent than somatostatin in inhibiting glucose-stimulated insulin release. In contrast, DC-23-99 (a type 5 receptor selective analog), which was previously found to be a more potent inhibitor of insulin secretion than somatostatin, had considerably less potent (EC50 410 nmole) effects on glucagon release. The SSTR3-specific ligands, DC-25-12 and DC-25-20, were not effective at the doses tested. The differing spectra of activities of these analogs suggest that inhibition of insulin and glucagon secretion in rats is mediated by entirely different somatostatin receptor populations.

01 Jan 1994·PeptidesQ3 · MEDICINE

Characterization of somatostatin receptor subtypes controlling rat gastric acid and pancreatic amylase release

Q3 · MEDICINE

Article

Author: D.H. Coy ; Z.-F. Gu ; R.T. Jensen ; W.J. Rossowski ; U.S. Akarca

An examination of the binding characteristics of a large number of somatostatin analogues with respect to the five known somatostatin receptor subtypes has recently resulted in the discovery of several peptides with some selectivity for types 2, 3, and 4 and little affinity for type 1 or 5 receptor. A panel of these peptides has thus far implicated type 2 receptors in the inhibition of release of pituitary growth hormone and type 4 receptors in inhibiting pancreatic insulin release. In the present article, we have examined the inhibitory effects of the same group of peptides on in vivo rat gastric acid and pancreatic amylase release and binding to rat pancreatic acinar cells. The type 2-selective ligand NC-8-12 was a potent inhibitor of gastric acid release (EC50s in the 1.5 nM region) whereas the type 4-selective ligand, DC-23-99, elicited little response. However, some involvement of type 3 receptors could not be ruled out because the type 3-selective analogue, DC-25-20, exhibited inhibitory effects at higher dose levels (EC50 > 10 nM). Conversely, the type 4 analogue was a potent inhibitor of amylase release (EC50 1.1 nM) whereas the type 3 analogue had no significant effects at doses tested. DC-23-99 also bound with high affinity to rat acinar cells (EC50 3.8 nM), whereas DC-25-20 exhibited more than 10-fold less affinity. Thus, these two major biological functions of somatostatin appear to be controlled by different receptors and, furthermore, effects on both endocrine and exocrine pancreas appear to be type 4 receptor mediated.

01 Dec 1993·Biochemical and Biophysical Research CommunicationsQ3 · BIOLOGY

Potent Inhibitory Effects of a Type Four Receptor-Selective Somatostatin Analog on Rat Insulin Release

Q3 · BIOLOGY

Article

Author: D.H. Coy ; W.J. Rossowski

A total of 5 somatostatin (SS) receptors have been characterized, cloned, and transfected into various cell types which have recently been used to discern peptide ligands displaying high degrees of selectivity for binding to types 2, 3, and 4. These have now allowed us to examine which receptor(s) is involved in SS inhibition of glucose-stimulated rat pancreatic insulin release. The type 4 selective ligand, DC-23-99, which had little affinity for receptor types 1, 2, or 5, was at least equipotent to SS in preventing insulin release. In contrast, the type 3 selective peptide, DC-25-20, was totally devoid of inhibitory effects. Peptides, such as NC-8-12, which have extremely high affinity for type 2 receptors but far less for types 1, 3, 4 and 5, were considerably less potent than SS in this assay. Thus, 2 major inhibitory physiological functions of SS on GH (type 2) and insulin release appear to be mediated by entirely different receptor types.

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