Deng Pan-Yue, Lei Saobo
Department of Pharmacology, Physiology and Therapeutics, School of Medicine and Health Sciences, University of North Dakota, Grand Forks, 58203, USA.
J Physiol. 2006 Apr 15;572(Pt 2):425-42. doi: 10.1113/jphysiol.2005.104463. Epub 2006 Feb 2.
Cholecystokinin (CCK) interacts with two types of G protein-coupled receptors in the brain: CCK-A and CCK-B receptors. Both CCK and CCK-B receptors are widely distributed in the hippocampal formation, but the functions of CCK there have been poorly understood. In the present study, we initially examined the effects of CCK on GABA(A) receptor-mediated synaptic transmission in the hippocampal formation and then explored the underlying cellular mechanisms by focusing on the dentate gyrus region, where the highest levels of CCK-binding sites have been detected. Our results indicate that activation of CCK-B receptors initially and transiently increased spontaneous IPSC (sIPSC) frequency, followed by a persistent reduction. The effects of CCK were more evident in juvenile rats, suggesting that they are developmentally regulated. Cholecystokinin failed to modulate the miniature IPSCs recorded in the presence of TTX and the amplitude of the evoked IPSCs, but produced a transient increase followed by a reduction in action potential firing frequency recorded from GABAergic interneurons, suggesting that CCK acts by modulating the excitability of the interneurons to regulate GABA release. Cholecystokinin reduced the amplitude of the after-hyperpolarization of the action potentials, and application of paxilline or charybdotoxin considerably reduced CCK-mediated modulation of sIPSC frequency, suggesting that the effects of CCK are related to the inhibition of Ca(2+)-activated K(+) currents (I(K(Ca))). The effects of CCK were independent of the functions of phospholipase C, intracellular Ca(2+) release, protein kinase C or phospholipase A(2), suggesting a direct coupling between the G proteins of CCK-B receptors and I(K(Ca)). Our results provide a novel mechanism underlying CCK-mediated modulation of GABA release.
胆囊收缩素（CCK）在大脑中与两种G蛋白偶联受体相互作用：CCK-A受体和CCK-B受体。CCK和CCK-B受体在海马结构中广泛分布，但CCK在那里的功能一直未得到充分了解。在本研究中，我们首先研究了CCK对海马结构中GABA(A)受体介导的突触传递的影响，然后通过聚焦于齿状回区域来探索潜在的细胞机制，在该区域检测到了最高水平的CCK结合位点。我们的结果表明，CCK-B受体的激活最初会短暂增加自发性抑制性突触后电流（sIPSC）频率，随后持续降低。CCK的作用在幼年大鼠中更为明显，表明它们受发育调节。胆囊收缩素未能调节在TTX存在下记录的微小抑制性突触后电流以及诱发的抑制性突触后电流的幅度，但会使从GABA能中间神经元记录的动作电位发放频率先短暂增加然后降低，这表明CCK通过调节中间神经元的兴奋性来调节GABA释放。胆囊收缩素降低了动作电位后超极化的幅度，应用鬼笔环肽或美洲箭毒素可显著降低CCK介导的对sIPSC频率的调节，这表明CCK的作用与抑制钙激活钾电流（I(K(Ca))）有关。CCK的作用独立于磷脂酶C、细胞内钙释放、蛋白激酶C或磷脂酶A(2)的功能，表明CCK-B受体的G蛋白与I(K(Ca))之间存在直接偶联。我们的结果为CCK介导的GABA释放调节提供了一种新机制。
