Some cannabinoid receptor ligands and their distomers are direct-acting openers of SUR1 K ATP channels

Christopher J. Lynch, Qing Zhou, Show Ling Shyng, David J. Heal, Sharon C. Cheetham, Keith Dickinson, Peter Gregory, Michael Firnges, Ulrich Nordheim, Stephanie Goshorn, Dania Reiche, Lechoslaw Turski, Jochen Antel

Research output: Contribution to journalArticle

9 Scopus citations

Abstract

Here, we examined the chronic effects of two cannabinoid receptor-1 (CB1) inverse agonists, rimonabant and ibipinabant, in hyperinsulinemic Zucker rats to determine their chronic effects on insulinemia. Rimonabant and ibipinabant (10 mg·kg -1·day -1) elicited body weightindependent improvements in insulinemia and glycemia during 10 wk of chronic treatment. To elucidate the mechanism of insulin lowering, acute in vivo and in vitro studies were then performed. Surprisingly, chronic treatment was not required for insulin lowering. In acute in vivo and in vitro studies, the CB1 inverse agonists exhibited acute K channel opener (KCO; e.g., diazoxide and NN414)-like effects on glucose tolerance and glucose-stimulated insulin secretion (GSIS) with approximately fivefold better potency than diazoxide. Followup studies implied that these effects were inconsistent with a CB1- mediated mechanism. Thus effects of several CB1 agonists, inverse agonists, and distomers during GTTs or GSIS studies using perifused rat islets were unpredictable from their known CB1 activities. In vivo rimonabant and ibipinabant caused glucose intolerance in CB1 but not SUR1-KO mice. Electrophysiological studies indicated that, compared with diazoxide, 3 μM rimonabant and ibipinabant are partial agonists for K channel opening. Partial agonism was consistent with data from radioligand binding assays designed to detect SUR1 K ATP KCOs where rimonabant and ibipinabant allosterically regulated 3Hglibenclamide- specific binding in the presence of MgATP, as did diazoxide and NN414. Our findings indicate that some CB1 ligands may directly bind and allosterically regulate Kir6.2/SUR1 K ATP channels like other KCOs. This mechanism appears to be compatible with and may contribute to their acute and chronic effects on GSIS and insulinemia.

Original languageEnglish (US)
Pages (from-to)E540-E551
JournalAmerican Journal of Physiology - Endocrinology and Metabolism
Volume302
Issue number5
DOIs
StatePublished - Mar 1 2012

Keywords

  • ATP-sensitive potassium channels
  • Diazoxide
  • Glibenclamide
  • Glucose-stimulated insulin secretion
  • Insulin
  • Oral glucose tolerance
  • Sulfonylurea receptor 1
  • Zucker rat

ASJC Scopus subject areas

  • Endocrinology, Diabetes and Metabolism
  • Physiology
  • Physiology (medical)

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    Lynch, C. J., Zhou, Q., Shyng, S. L., Heal, D. J., Cheetham, S. C., Dickinson, K., Gregory, P., Firnges, M., Nordheim, U., Goshorn, S., Reiche, D., Turski, L., & Antel, J. (2012). Some cannabinoid receptor ligands and their distomers are direct-acting openers of SUR1 K ATP channels. American Journal of Physiology - Endocrinology and Metabolism, 302(5), E540-E551. https://doi.org/10.1152/ajpendo.00250.2011