Cellular Neurobiology Branch, Electrophysiology Research Section, National Institute on Drug Abuse, National Institutes of Health, Baltimore, MD 21224, USA.
Biochem Biophys Res Commun. 2012 Jun 22;423(1):13-8. doi: 10.1016/j.bbrc.2012.05.042. Epub 2012 May 15.
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.
内源性大麻素系统已被证明在胰腺β细胞中活跃。然而，内源性大麻素（ECs）对胰岛素分泌的影响尚未明确，并且可能因β细胞的代谢状态而异。具体来说，尚不清楚 ECs 的作用是否通过大麻素受体的激活或通过它们与β细胞的离子通道的直接相互作用发生。为了开始描绘 ECs 对β细胞功能的影响，我们研究了在没有葡萄糖刺激的情况下，EC 2-AG 如何影响β细胞离子通道。使用小鼠胰岛素瘤细胞系 R7T1 通过全细胞膜片钳记录来检测 2-AG 对高电压激活（HVA）钙、延迟整流（K（v））和 ATP 敏感的 K（K（ATP））通道的影响。在 2mM 葡萄糖下，2-AG 抑制 HVA 钙（其中大部分是 L 型通道）、K（v）和 K（ATP）通道。对 2-AG 阻断最敏感的通道是 K（ATP）通道，其中 2-AG 的 IC50 为 1μM。药理试剂表明，所有这些通道的阻断均与大麻素受体无关。我们的结果为先前的观察结果提供了一种机制，即 CB1R 激动剂通过 CB1R 独立阻断 K（ATP）通道，在低血糖浓度下增加胰岛素分泌。
