Department of Pharmacology, Physiology and Therapeutics, School of Medicine and Health Sciences, University of North Dakota, Grand Forks, ND 58203, USA.
J Neurophysiol. 2011 Sep;106(3):1515-24. doi: 10.1152/jn.00025.2011. Epub 2011 Jul 13.
Cholecystokinin (CCK) is one of the most abundant neuropeptides in the brain, where it interacts with two G protein-coupled receptors (CCK-1 and CCK-2). Activation of both CCK receptors increases the activity of PLC, resulting in increases in intracellular calcium ion (Ca(2+)) release and activation of PKC. Whereas high density of CCK receptors has been detected in the superficial layers of the entorhinal cortex (EC), the functions of CCK in this brain region have not been determined. Here, we studied the effects of CCK on neuronal excitability of layer III pyramidal neurons in the EC. Our results showed that CCK remarkably increased the firing frequency of action potentials (APs). The effects of CCK on neuronal excitability were mediated via activation of CCK-2 receptors and required the functions of G proteins and PLC. However, CCK-mediated facilitation of neuronal excitability was independent of inositol trisphosphate receptors and PKC. CCK facilitated neuronal excitability by activating a cationic channel to generate membrane depolarization. The effects of CCK were suppressed by the generic, nonselective cationic channel blockers, 2-aminoethyldiphenyl borate and flufenamic acid, but potentiated by gadolinium ion and lanthanum ion at 100 μM. Depletion of extracellular Ca(2+) also counteracted CCK-induced increases in AC firing frequency. Moreover, CCK-induced enhancement of neuronal excitability was inhibited significantly by intracellular application of the antibody to transient receptor potential channel 5 (TRPC5), suggesting the involvement of TRPC5 channels. Our results provide a cellular and molecular mechanism to help explain the functions of CCK in vivo.
胆囊收缩素（CCK）是大脑中最丰富的神经肽之一，它与两种 G 蛋白偶联受体（CCK-1 和 CCK-2）相互作用。两种 CCK 受体的激活都会增加 PLC 的活性，导致细胞内钙离子（Ca(2+)）释放增加和 PKC 的激活。虽然在海马回的浅层（EC）中检测到高密度的 CCK 受体，但 CCK 在该脑区的功能尚未确定。在这里，我们研究了 CCK 对 EC 中 III 层锥体神经元兴奋性的影响。我们的结果表明，CCK 显著增加了动作电位（AP）的发射频率。CCK 对神经元兴奋性的影响是通过激活 CCK-2 受体介导的，需要 G 蛋白和 PLC 的功能。然而，CCK 介导的神经元兴奋性增加与三磷酸肌醇受体和 PKC 无关。CCK 通过激活阳离子通道产生膜去极化来促进神经元兴奋性。CCK 的作用可被通用的非选择性阳离子通道阻滞剂 2-氨基乙基二苯基硼酸酯和氟芬那酸抑制，但可被 100μM 的钆离子和镧离子增强。细胞外 Ca(2+)的耗竭也会抵消 CCK 引起的 AC 放电频率增加。此外，细胞内应用瞬时受体电位通道 5（TRPC5）的抗体显著抑制了 CCK 诱导的神经元兴奋性增强，表明 TRPC5 通道的参与。我们的结果提供了一种细胞和分子机制，有助于解释 CCK 在体内的功能。
