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

7 Citations (Scopus)

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)
JournalAmerican Journal of Physiology - Endocrinology and Metabolism
Volume302
Issue number5
DOIs
StatePublished - Mar 2012

Fingerprint

rimonabant
Cannabinoid Receptors
Diazoxide
Adenosine Triphosphate
Ligands
Insulin
Glucose
Cannabinoid Receptor Agonists
Zucker Rats
Radioligand Assay
Glucose Intolerance
ibipinabant

Keywords

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

ASJC Scopus subject areas

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

Cite this

Some cannabinoid receptor ligands and their distomers are direct-acting openers of SUR1 K ATP channels. / Lynch, Christopher J.; Zhou, Qing; Shyng, Show-Ling; Heal, David J.; Cheetham, Sharon C.; Dickinson, Keith; Gregory, Peter; Firnges, Michael; Nordheim, Ulrich; Goshorn, Stephanie; Reiche, Dania; Turski, Lechoslaw; Antel, Jochen.

In: American Journal of Physiology - Endocrinology and Metabolism, Vol. 302, No. 5, 03.2012.

Research output: Contribution to journalArticle

Lynch, CJ, Zhou, Q, Shyng, S-L, Heal, DJ, Cheetham, SC, 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, vol. 302, no. 5. https://doi.org/10.1152/ajpendo.00250.2011
Lynch, Christopher J. ; Zhou, Qing ; Shyng, Show-Ling ; Heal, David J. ; Cheetham, Sharon C. ; Dickinson, Keith ; Gregory, Peter ; Firnges, Michael ; Nordheim, Ulrich ; Goshorn, Stephanie ; Reiche, Dania ; Turski, Lechoslaw ; Antel, Jochen. / Some cannabinoid receptor ligands and their distomers are direct-acting openers of SUR1 K ATP channels. In: American Journal of Physiology - Endocrinology and Metabolism. 2012 ; Vol. 302, No. 5.
@article{4a478b32c7e04b299aad91a7d6338021,
title = "Some cannabinoid receptor ligands and their distomers are direct-acting openers of SUR1 K ATP channels",
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.",
keywords = "ATP-sensitive potassium channels, Diazoxide, Glibenclamide, Glucose-stimulated insulin secretion, Insulin, Oral glucose tolerance, Sulfonylurea receptor 1, Zucker rat",
author = "Lynch, {Christopher J.} and Qing Zhou and Show-Ling Shyng and Heal, {David J.} and Cheetham, {Sharon C.} and Keith Dickinson and Peter Gregory and Michael Firnges and Ulrich Nordheim and Stephanie Goshorn and Dania Reiche and Lechoslaw Turski and Jochen Antel",
year = "2012",
month = "3",
doi = "10.1152/ajpendo.00250.2011",
language = "English (US)",
volume = "302",
journal = "American Journal of Physiology - Renal Fluid and Electrolyte Physiology",
issn = "1931-857X",
publisher = "American Physiological Society",
number = "5",

}

TY - JOUR

T1 - Some cannabinoid receptor ligands and their distomers are direct-acting openers of SUR1 K ATP channels

AU - Lynch, Christopher J.

AU - Zhou, Qing

AU - Shyng, Show-Ling

AU - Heal, David J.

AU - Cheetham, Sharon C.

AU - Dickinson, Keith

AU - Gregory, Peter

AU - Firnges, Michael

AU - Nordheim, Ulrich

AU - Goshorn, Stephanie

AU - Reiche, Dania

AU - Turski, Lechoslaw

AU - Antel, Jochen

PY - 2012/3

Y1 - 2012/3

N2 - 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.

AB - 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.

KW - ATP-sensitive potassium channels

KW - Diazoxide

KW - Glibenclamide

KW - Glucose-stimulated insulin secretion

KW - Insulin

KW - Oral glucose tolerance

KW - Sulfonylurea receptor 1

KW - Zucker rat

UR - http://www.scopus.com/inward/record.url?scp=84857283869&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84857283869&partnerID=8YFLogxK

U2 - 10.1152/ajpendo.00250.2011

DO - 10.1152/ajpendo.00250.2011

M3 - Article

VL - 302

JO - American Journal of Physiology - Renal Fluid and Electrolyte Physiology

JF - American Journal of Physiology - Renal Fluid and Electrolyte Physiology

SN - 1931-857X

IS - 5

ER -