CLONIDINE-DISPLACING SUBSTANCE AND IRS PUTATIVE ROLE IN CONTROL OF INSULIN-SECRETION - A MINIREVIEW

1. Imidazoline binding sites, or I-sites, are a class of recently defi ned nonadrenoceptor recognition sites whose most potent ligands are im idazolines and related compounds. 2. The pancreatic islet beta-cell I- site, which mediates imidazoline induced stimulation of insulin re lea se, appears to be the first site to be pharmacologically defined with selective agonists and antagonists. 3. The natural ligand for imidazol ine recognition sites is still unknown. The strongest candidate is clo nidine displacing substance (CDS), originally identified in extracts o f rat and bovine brain. However, the bioactive molecule has not been i dentified definitively. Agmatine, a decarboxylated derivative of argin ine, also binds to both I-sites and alpha(2)-adrenoceptors (Li ct al., 1994), and is, by definition, a CDS molecule. 4. In the endocrine pan creas, agmatine is a weak insulin secretagogue, which induces a slowly developing secretory response. However, this profile does not correla te with interaction at the islet I-site, and thus agmatine is unlikely to be an endogenous secretagogue acting functionally at the islet I s ite. 5. Crude preparations of CDS from rat brain can potentiate glucos e-induced insulin release and re verse the effects of diazoxide in rat and human islets of Langerhans. These two effects are also subject to blockade by the imidazoline antagonists RX801080 and KU1R. Furthermor e, islets that were desensitized to the effects of the imidazoline sec retagogue efaroxan (after 18-hr culture with imidazoline) were refract ory to the actions of CDS, 6. Overall, CDS displays many characteristi cs expected of an endogenous regulator of insulin secretion acting thr ough the islet beta-cell imidazoline site. This evidence strengthens t he hypothesis that the islet beta-cell imidazoline site mediating cont rol of insulin release in the endocrine pancreas is a biologically rel evant receptor. Furthermore, a physiological role of CDS in the endocr ine pancreas cannot be excluded. (C) 1998 Elsevier Science Inc.