A range of imidazoline derivatives are known to be effective stimulators of insulin secretion, and this response correlates with closure of ATP-sensitive potassium channels in the pancreatic beta-cell. However, mounting evidence indicates that potassium channel blockade may form only part of the mechanism by which imidazolines exert their effects on insulin secretion. Additionally, it remains unclear whether members of this class of drugs can bind directly to potassium channel components and whether occupation of a single binding site accounts for their functional activity. This review considers recent developments in the field and highlights evidence that does not fit readily with the concept that a single mechanism of action is sufficient to mediate the effects of imidazolines on pancreatic hormone secretion.
We have employed an amino derivative of the imidazoline ligand, efaroxan, to isolate imidazoline binding proteins from solubilised extracts of rat brain, by affinity chromatography. A number of proteins were specifically retained on the affinity column and one of these was immunoreactive with an antiserum raised against the ion conducting pore component of the ATP-sensitive potassium channel. Patch clamp experiments confirmed that, like its parent compound, amino-efaroxan blocks ATP-sensitive potassium channels in human pancreatic L Lcells and can stimulate the insulin secretion from these cells. The results reveal that a member of the ion conducting pore component family is strongly associated with imidazoline binding proteins in brain and in the endocrine pancreas.z 1999 Federation of European Biochemical Societies.
1 Efaroxan induces membrane depolarization by interaction with the pore forming subunit of the ATP-sensitive potassium channel, Kir6.2. However, this eect is not responsible for its full secretory activity. 2 In this study we have used an anti-idiotypic approach to generate antibodies that recognize additional proteins that may be regulated by efaroxan in pancreatic b-cells. 3 Using these antisera in an expression cloning strategy we have identi®ed a monomeric GTPbinding protein, Rhes, as a potential target for regulation by imidazoline ligands. Rhes is shown to be expressed in b-cells and its expression is regulated by efaroxan under conditions when a structurally related molecule, KU14R, is ineective. 4 The results reveal that b-cells express Rhes and suggest that changes in the expression of this molecule may regulate the sensitivity of b-cells to imidazoline secretagogues.
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