title: Blockade of β-cell K(ATP) channels by the endocannabinoid, 2-arachidonoylglycerol.
abstract: The endocannabinoid system has been demonstrated to be active in the pancreatic β-cell. However the effects of the endocannabinoids (ECs) on insulin secretion are not well defined and may vary depending on the metabolic state of the β-cell. Specifically it is not known whether the effects of the ECs occur by activation of the cannabinoid receptors or via their direct interaction with the ion channels of the β-cell. To begin to delineate the effects of ECs on β-cell function, we examined how the EC, 2-AG influences β-cell ion channels in the absence of glucose stimulation. The mouse insulinoma cell line R7T1 was used to survey the effects of 2-AG on the high voltage activated (HVA) calcium, the delayed rectifier (K(v)), and the ATP-sensitive K (K(ATP)) channels by whole cell patch clamp recording. At 2mM glucose, 2-AG inhibited the HVA calcium (the majority of which are L-type channels), K(v), and K(ATP) channels. The channel exhibiting the most sensitivity to 2-AG blockade was the K(ATP) channel, where the IC(50) for 2-AG was 1 μM. Pharmacological agents revealed that the blockade of all these channels was independent of cannabinoid receptors. Our results provide a mechanism for the previous observations that CB1R agonists increase insulin secretion at low glucose concentrations through CB1R independent blockade of the K(ATP) channel.
authors.affiliation: Cellular Neurobiology Branch, Electrophysiology Research Section, National Institute on Drug Abuse, National Institutes of Health, Baltimore, MD 21224, USA.
authors.forename: Charles E
authors.initials: CE
authors.lastname: Spivak
authors.forename: Wook
authors.initials: W
authors.lastname: Kim
authors.forename: Qing-Rong
authors.initials: QR
authors.lastname: Liu
authors.forename: Carl R
authors.initials: CR
authors.lastname: Lupica
authors.forename: Máire E
authors.initials: ME
authors.lastname: Doyle
mesh_terms: D000818:Animals; D001095:Arachidonic Acids / Q000494:pharmacology*; D002118:Calcium / Q000378:metabolism; D063385:Cannabinoid Receptor Modulators / Q000494:pharmacology*; D045744:Cell Line, Tumor; D063388:Endocannabinoids; D005947:Glucose / Q000494:pharmacology; D005989:Glycerides / Q000494:pharmacology*; D007328:Insulin / Q000378:metabolism*; D000078790:Insulin Secretion; D050417:Insulin-Secreting Cells / Q000187:drug effects* / Q000378:metabolism; D054086:KATP Channels / Q000037:antagonists & inhibitors*; D051379:Mice; D018408:Patch-Clamp Techniques; D043884:Receptor, Cannabinoid, CB1 / Q000819:agonists / Q000378:metabolism
chemical_list: D001095:Arachidonic Acids; D063385:Cannabinoid Receptor Modulators; D063388:Endocannabinoids; D005989:Glycerides; D007328:Insulin; D054086:KATP Channels; D043884:Receptor, Cannabinoid, CB1; C094503:glyceryl 2-arachidonate; D005947:Glucose; D002118:Calcium