Gastrointestinal Diseases Research Unit (GIDRU), Department of Medicine, Queen's University, Kingston, ON, Canada.
Neurogastroenterol Motil. 2010 Apr;22(4):470-9, e111. doi: 10.1111/j.1365-2982.2009.01430.x. Epub 2009 Dec 11.
Glucagon-like peptide-1 (GLP-1) is a major hormone known to regulate glucose homeostasis and gut function, and is an important satiety mediator. These actions are at least in part mediated via an action on vagal afferent neurons. However, the mechanism by which GLP-1 activates vagal afferents remains unknown. We hypothesized that GLP-1 acts on nodose ganglion neuron voltage-gated potassium (KV) channels, increasing membrane excitability.
Employing perforated patch clamp recordings we examined the effects of GLP-1 on membrane properties as well as voltage-gated potassium currents. Extracellular recordings of jejunal afferents were performed to demonstrate the functional relevance of these effects at the nerve terminal.
Glucagon-like peptide-1 depolarized a subpopulation of nodose neurons. This membrane depolarization was used to identify neurons containing functional GLP-1 receptors. In these neurons, GLP-1 decreased rheobase and broadened the action potential, and increased the number of action potentials elicited at twice rheobase. We identified a GLP-1 sensitive current whose reversal potential shifted in a depolarizing direction when extracellular potassium was increased. We identified two macroscopic K currents, IA, an inactivating current and IK a sustained current. GLP-1 caused inhibition of these currents, IK by 45%, P < 0.05 and IA currents by 52%P < 0.01, associated with a hyperpolarizing shift of steady-state inactivation curves for both currents. In extracellular recordings of jejunal afferents, GLP-1 increased firing rate, the effect blocked by the K(+) channel antagonist 4-AP.
CONCLUSIONS & INFERENCES: These experiments indicate that GLP-1 receptor activation results in vagal afferent excitation, due at least in part to inhibition of sustained and inactivating potassium currents. This mechanism may be important in satiety and glucose homeostatic signals arising from the gastrointestinal tract.
胰高血糖素样肽-1（GLP-1）是一种主要的激素，已知其能调节葡萄糖稳态和肠道功能，是一种重要的饱腹感介质。这些作用至少部分是通过对迷走传入神经元的作用来介导的。然而，GLP-1 激活迷走传入神经元的机制尚不清楚。我们假设 GLP-1 作用于结状神经节神经元电压门控钾 (KV) 通道，增加膜兴奋性。
我们采用穿孔膜片钳记录技术，研究了 GLP-1 对膜特性和电压门控钾电流的影响。通过记录空肠传入神经的细胞外记录，证明了这些作用在神经末梢的功能相关性。
GLP-1 使一部分结状神经元去极化。这种膜去极化被用来识别含有功能性 GLP-1 受体的神经元。在这些神经元中，GLP-1 降低了阈强度并拓宽了动作电位，并增加了两倍阈强度激发的动作电位数量。我们鉴定了一种对 GLP-1 敏感的电流，当细胞外钾增加时，其反转电位向去极化方向移动。我们鉴定了两种宏观 K 电流，IA，一种失活电流和 IK a 持续电流。GLP-1 引起这些电流的抑制，即 IK 减少 45%，P < 0.05，IA 电流减少 52%，P < 0.01，同时两种电流的稳态失活曲线都发生超极化移位。在空肠传入神经的细胞外记录中，GLP-1 增加了放电频率，该作用被 K(+)通道拮抗剂 4-AP 阻断。
这些实验表明，GLP-1 受体的激活导致迷走传入神经兴奋，至少部分原因是抑制持续和失活钾电流。这种机制可能在胃肠道产生的饱腹感和葡萄糖稳态信号中很重要。
