title: Effect of insulinotropic agent nateglinide on Kv and Ca(2+) channels in pancreatic beta-cell.
abstract: Novel insulinotropic agent nateglinide stimulates insulin via binding to sulfonylurea receptor and closing the ATP-dependent K+ (K(ATP)) channels in pancreatic beta-cells, leading to an increase in [Ca(2+)](i) for exocytosis. The voltage-dependent Ca(2+) channel and the delayed rectifier K+ (Kv) channels are also present in beta-cells and their activities determine the configuration of action potential and hence contribute to the regulation of [Ca(2+)](i) and insulin secretion. This study, by using the patch-clamp method in whole cell configuration, comparatively characterized the direct effects of sulfonylurea receptor ligands including nateglinide, glyburide, and repaglinide on Kv and Ca(2+) channels. Each agent inhibited Kv currents in a concentration-dependent manner with effective concentration range two to three orders higher than that for blocking K(ATP) channels. A marginal stimulation of Ca(2+) current was observed with all drugs, while repaglinide at concentration greater than 300 nM inhibited Ca(2+) current. The direct effects of these antidiabetic agents on Kv and Ca(2+) channels may act concertedly with their primary action on K(ATP) channels in regulating [Ca(2+)](i) and the stimulus-secretion coupling.
authors.affiliation: Metabolic/Cardiovascular Diseases, Novartis Institute for Biomedical Research, 556 Morris Avenue, Summit, NJ 07901, USA. shiling.hu@pharma.novartis.com
authors.forename: S
authors.initials: S
authors.lastname: Hu
authors.forename: S
authors.initials: S
authors.lastname: Wang
mesh_terms: D000818:Animals; D015220:Calcium Channels / Q000502:physiology*; D002219:Carbamates / Q000494:pharmacology; D003510:Cyclohexanes / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004558:Electric Stimulation; D005905:Glyburide / Q000494:pharmacology; D007004:Hypoglycemic Agents / Q000494:pharmacology; D007328:Insulin / Q000378:metabolism*; D000078790:Insulin Secretion; D007515:Islets of Langerhans / Q000187:drug effects* / Q000378:metabolism / Q000502:physiology; D008297:Male; D008564:Membrane Potentials / Q000187:drug effects; D000077715:Nateglinide; D018408:Patch-Clamp Techniques; D010649:Phenylalanine / Q000031:analogs & derivatives / Q000494:pharmacology*; D010880:Piperidines / Q000494:pharmacology; D015221:Potassium Channels / Q000502:physiology*; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D015220:Calcium Channels; D002219:Carbamates; D003510:Cyclohexanes; D007004:Hypoglycemic Agents; D007328:Insulin; D010880:Piperidines; D015221:Potassium Channels; D000077715:Nateglinide; D010649:Phenylalanine; C072379:repaglinide; D005905:Glyburide