Blockade of β-cell KATP 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 (Kv), and the ATP-sensitive K (KATP) channels by whole cell patch clamp recording. At 2mM glucose, 2-AG inhibited the HVA calcium (the majority of which are L-type channels), Kv, and KATP channels. The channel exhibiting the most sensitivity to 2-AG blockade was the KATP channel, where the IC50 for 2-AG was 1μM. 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 KATP channel.