The endocannabinoid system has been demonstrated to be active in the pancreatic beta-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 beta-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 beta-cell. To begin to delineate the effects of ECs on beta-cell function, we examined how the EC, 2-AG influences beta-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 2 mM 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 IC50 for 2-AG was 1 mu M. 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. (C) 2012 Elsevier Inc. All rights reserved.