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Comparative Effects of Efaroxan and b-Carbolines on the Secretory Activity of Rodent and Human b Cells
aInstitute of Biomedical and Clinical Science, Peninsula Medical School, Plymouth, Devon PL6 8BX, UK bSchool of Life Sciences, Keele University, Keele ST5 5BG, UK cBiomedical Research Institute, University of Warwick, Coventry CV4 7AL, UK dPsychopharmacology Unit, University of Bristol, Bristol BS8 1TS, UK
Address for correspondence: Prof. N.G. Morgan, Room N32, ITTC Building, Peninsula Medical School, Tamar Science Park, Plymouth, Devon PL6 8BX, UK. Voice: (+44) 1752-764274; fax: (+44) 1752-764234. e-mail: noel.morgan{at}pms.ac.uk Ann. N.Y. Acad. Sci. 1009: 167-174 (2003).
The pancreatic b-cell expresses an imidazoline-binding site that is involved in the regulation of insulin secretion. This site is pharmacologically atypical in comparison with the I1 and I2 sites described in other tissues, and it has been classified as I3. The structural requirements for binding of ligands to the I3 site have not been fully defined, although a range of synthetic I3 ligands have been characterized in functional terms. Evidence has been presented that an endogenous I3 ligand may exist, because extracts of brain contain an active principle that stimulates insulin secretion in a manner consistent with the involvement of I3 sites. The active component has not been identified but has been equated with the long-sought clonidine displacing substance (CDS) that is proposed as the endogenous ligand for imidazoline-binding sites. Recent evidence has indicated that one active component of CDS may be a b-carboline, but it is not known whether b-carbolines can stimulate insulin secretion. Thus, we have studied the effects of b-carbolines on insulin secretion and cytosolic Ca21 levels in rodent and human islet cells. The results reveal that harmane, pinoline, and norharmane cause a dose- and glucose-dependent increase in insulin secretion but show that this response differs in a number of ways from that elicited by the well-characterized I3-agonist, efaroxan. Thus, b-carbolines represent a new class of insulin secretagogues, although it remains unclear whether their action is mediated solely by I3 sites in the b cell.
Key Words: efaroxan • harmane • I3-binding sites • b-cell • insulin secretion • islets of Langerhans
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