van Gassen K L I, Netzeband J G, de Graan P N E, Gruol D L
Department of Neuropharmacology, CVN-11, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA.
Eur J Neurosci. 2005 Jun;21(11):2949-57. doi: 10.1111/j.1460-9568.2005.04113.x.
The chemokine CCL2 is produced at high levels in the central nervous system (CNS) during infection, injury, neuroinflammation and other pathological conditions. Cells of the CNS including neurons and glia express receptors for CCL2 and these receptors may contribute to a signaling system through which pathologic conditions in the CNS are communicated. However, our understanding of the consequences of activation of chemokine signaling in the CNS is limited, especially for neurons. In many cell types, chemokine signaling alters intracellular Ca(2+) dynamics. Therefore, we investigated the potential involvement of this mechanism in neuronal signaling activated by CCL2. In addition, we examined the effects of CCL2 on neuronal excitability. The studies focused on the rat cerebellar Purkinje neuron, an identified CNS neuronal type reported to express both CCL2 and its receptor, CCR2. Immunohistochemical studies of Purkinje neurons in situ confirmed that they express CCR2 and CCL2. The effect of exogenous application on Purkinje neurons was studied in a cerebellar culture preparation. CCL2 was tested by micropressure or bath application, at high concentrations (13-100 nm) to simulate conditions during a pathologic state. Results show that Purkinje neurons express receptors for CCL2 and that activation of these receptors alters several neuronal properties. CCL2 increased resting Ca(2+) levels, enhanced the Ca(2+) response evoked by activation of metabotropic glutamate receptor 1 and depressed action potential generation in the cultured Purkinje neurons. Passive membrane properties were unaltered. These modulatory effects of CCL2 on neuronal properties are likely to contribute to the altered CNS function associated with CNS disease and injury.
趋化因子CCL2在感染、损伤、神经炎症及其他病理状态下会在中枢神经系统（CNS）中高水平产生。中枢神经系统的细胞，包括神经元和神经胶质细胞，表达CCL2的受体，这些受体可能构成一个信号系统，通过该系统传递中枢神经系统的病理状态。然而，我们对中枢神经系统中趋化因子信号激活后果的了解有限，尤其是对于神经元。在许多细胞类型中，趋化因子信号会改变细胞内Ca(2+)动力学。因此，我们研究了该机制在CCL2激活的神经元信号中的潜在作用。此外，我们还研究了CCL2对神经元兴奋性的影响。研究聚焦于大鼠小脑浦肯野神经元，这是一种已确定的中枢神经系统神经元类型，据报道它同时表达CCL2及其受体CCR2。对原位浦肯野神经元的免疫组织化学研究证实它们表达CCR2和CCL2。在小脑培养制剂中研究了外源性应用对浦肯野神经元的影响。通过微压或浴槽给药方式，以高浓度（13 - 100 nM）测试CCL2，以模拟病理状态下的情况。结果表明，浦肯野神经元表达CCL2的受体，这些受体的激活会改变几种神经元特性。CCL2增加了静息Ca(2+)水平，增强了代谢型谷氨酸受体1激活所诱发的Ca(2+)反应，并抑制了培养的浦肯野神经元的动作电位产生。被动膜特性未改变。CCL2对神经元特性的这些调节作用可能导致与中枢神经系统疾病和损伤相关的中枢神经系统功能改变。
