It is now well established that many tissues express binding sites that are defined pharmacologically as “imidazoline” receptors. These are still undergoing full molecular characterisation but candidate clones have been identified for both the I 1 and I2 subtypes. The physiological roles of these receptors remain to be the subject of continuing investigation although there is strong evidence that I1 sites play a role in the central regulation of blood pressure while I2 sites may control feeding and other aspects of behaviour. In molecular terms, the third imidazoline receptor subtype (I3) is the least well characterised although progress in understanding its functional pharmacology is continuing. This receptor plays a role in the regulation of insulin secretion and mediates glucose-dependent increases in secretion in response to synthetic ligands such as efaroxan and antazoline. These agents were originally developed as selective α2-adrenoceptor antagonists but it is now clear that they also act as I3 agonists. Molecular characterisation of the functional activity of I3 agonists has been complicated by the fact that most of the ligands also interact with other cellular proteins, leading to potential difficulties in the interpretation of experimental data. In particular, it was established more than a decade ago that many I3-agonists induce the closure of ATP-sensitive potassium (KATP) channels and it is now clear that an imidazoline binding site is located within the pore-forming subunit (Kir6.2) of the KATP channel. However, increasing evidence implies that closure of this channel is not primarily responsible for the ability of imidazoline drugs to enhance insulin secretion. In support of this, imidazoline compounds have recently been described that do not close KATP channels but which potentiate insulin secretion very effectively. These probably interact with intracellular targets within pancreatic β- cells and the results suggest that the I3 receptor may be distinct from the imidazoline binding site associated with Kir6.2. Rather, the I3-site appears to control a distal step in the exocytotic pathway. The present review examines recent progress in identifying the I 3 receptor and describes the pharmacology of I3-agonists that regulate insulin secretion. The possibility that these agonists might then serve as prototypes for the development of novel ligands having therapeutic potential is also considered.
Keywords: type 2 diabetes, imidazoline receptors, efaroxan, clonidine-displacing substance, islets of langerhans, insulin secretion, glucagon secretion
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