代谢型谷氨酸受体与应激损伤

代谢型谷氨酸受体 (mGluRs)在应激性损伤中的作用日益受到重视 ,它可参与GC水平的调节 ,影响谷氨酸神经毒性作用和突触可塑性 (LTP、LTD)的诱导 ,由此表明mGluRs在应激性损伤中可能占有重要的地位。由于不同类型的mGluRs具有不同的作用 ,机制较为复杂 ,因此 ,今后还需进一步加强mGluRs与应激性损伤关系的研究     

代谢性谷氨酸受体药理学研究进展

代谢性谷氨酸受体是一组G是蛋白偶联的受体家族,各种亚型在中枢神经系统的分布、分子生物学和药理学特征不同。代谢性谷氨酸受体可以广泛精细调节神经系统功能。药理学研究发现,该受体与许多中枢系统疾病发病机制有关,在脑缺血、神经元坏死和凋亡、癫痫、精神分裂症、焦虑等方面具有成为药物作用靶点的潜力。     

Ⅱ、Ⅲ组亲代谢型谷氨酸受体激动剂逆转1-甲基-4-苯基吡啶离子抑制C6胶质瘤细胞摄取谷氨酸

目的：探讨Ⅱ、Ⅲ组亲代谢型谷氨酸受体(metabotropic glutamate receptors，mGluRs)激动剂对1-甲基-4-苯基吡啶离子(1-metyl-4-phenylpyridinium，MPP~ )抑制C6胶质瘤细胞摄取谷氨酸(glutamate，Glu)的影响。方法：应用同位素标记法测定C6胶质瘤细胞对培养液中[~3H]-D，L-谷氨酸的摄取。结果：Ⅱ组mGluRs激动剂(2S，2’R，3’R)-2-(2’，3’-di-carboxycyclopropyl)glycine(DCG-Ⅳ)和Ⅲ组mGluRs激动刺L( )-2-amino-4-phosphonobutyric acid(LAP4)100μmol·L~(-1)可以逆转MPP~ 抑制C6胶质瘤细胞摄取Glu的作用，而Ⅱ组mGluRs拮抗剂(RS)-1-Amino-5-phosphonoinan-1-carboxylic acid(APICA)和Ⅲ组mGluRs拮抗剂(RS)-α-methvlserine-O-phosphate(MSOP)可以完全阻断其激动剂的逆转作用。 结论：激活C6胶质瘤细胞上的Ⅱ、Ⅲ组mGluRs可以通过促进谷氨酸转运体摄取Glu、进而降低细胞外液的Glu浓度。     

Ⅱ、Ⅲ组亲代型谷氨酸受体激动剂对6-羟基多巴诱导的PC12细胞毒性无保护作用

阐明Ⅱ、Ⅲ组亲代谢型谷氨酸受体(metabotropic glutamate receptors,mGluRs)激动剂对6—羟基多巴(6-hydroxydopamine,6-OHDA)诱导的PC12细胞毒性是否具有保护作用。方法：应用高效液相色谱仪联用荧光检测技术测定谷氨酸浓度，应用四甲基偶氮唑盐(MTT)比色法测定PC12细胞活性。结果：6—OHDA剂量依赖性地诱导PC12细胞释放谷氨酸、减低细胞活性，Ⅱ组mGluRs激动剂DCG—IV和Ⅲ组mGluRs激动剂L-AP4对6—0HDA诱导的PC12细胞释放谷氨酸和细胞活性的降低均无显影响。结论：6—OHDA对多巴胺神经元的损伤作用与其诱导谷氨酸过度释放及其继发的兴奋性神经毒性有关，Ⅱ、Ⅲ组亲代谢型谷氨酸受体激动剂对6—OHDA诱导的PC12细胞毒性无保护作用。     

Ⅱ、Ⅲ组亲代谢型谷氨酸受体激动剂对脂多糖抑制C6胶质瘤细胞摄取谷氨酸的影响

目的探讨Ⅱ、Ⅲ组亲代谢型谷氨酸受体(metabotropic glutamate receptors, mGluRs)激动剂对脂多糖(LPS)抑制C6胶质瘤细胞摄取谷氨酸(glutamate, Glu)的影响.方法应用同位素标记法测定C6胶质瘤细胞对[3H]-D,L-Glu的摄取.应用Hoechst染色法、噻唑蓝比色法(MTT)分别检测C6胶质瘤细胞的凋亡、细胞活力.结果LPS(4、6 μg/Ml)显著抑制C6胶质瘤细胞摄取[3H]-D,L-Glu,抑制率分别达 17.6%和 22.2%.Ⅱ组mGluRs激动剂 DCG-Ⅳ 100 μmol/L 和Ⅲ组mGluRs激动剂L-AP4 100 μmol/L 逆转LPS对C6胶质瘤细胞摄取[3H]-D,L-Glu的抑制作用,这种逆转作用分别被Ⅱ、Ⅲ组mGluRs拮抗剂 APICA和MSOP取消.结论DCG-Ⅳ和L-AP4逆转LPS引起的C6胶质瘤细胞Glu摄取抑制,提示Ⅱ、Ⅲ组mGluRs激动剂通过促进Glu摄取,降低细胞外Glu浓度,从而发挥神经保护作用.     

亲代谢型谷氨酸受体配基对黑质6-羟基多巴损毁大鼠的抗氧化作用

目的　探讨亲代谢型谷氨酸受体 (mGluRs)配基对帕金森病 (PD )模型大鼠的抗氧化作用。方法　采用 6 羟基多巴单侧黑质损毁建立帕金森病大鼠模型 ,应用化学比色法测定血清总抗氧化能力 (T AOC)、抑制活性氧能力 (ROS)和谷胱甘肽 (GSH )含量。结果　与模型对照组相比 ,Ⅰ组mGluRs拮抗剂 (SIB 1893 ) ,Ⅱ组mGluRs激动剂 (APDC) ,Ⅲ组mGluRs激动剂 (L SOP )和L DOPA均能增加血清T AOC和GSH水平 ,提高清除ROS能力 ,尤以APDC组作用最明显。结论　Ⅰ组mGluRs拮抗剂和Ⅱ、Ⅲ组mGluRs激动剂对 6 羟基多巴损毁大鼠具有部分抗氧化功能 ,有利于机体减轻氧化应激所致的损伤     

Ⅱ、Ⅲ组亲代谢型谷氨酸受体激动剂逆转1-甲基-4-苯基吡啶离子抑制星形胶质细胞摄取谷氨酸

目的 :探讨Ⅱ、Ⅲ组亲代谢型谷氨酸受体(metabotropicglutamatereceptors ,mGluRs)激动剂对 1 甲基 4 苯基吡啶离子 (1 methyl 4 phenylpyridinium ,MPP )抑制星形胶质细胞摄取谷氨酸 (Glu)的影响。方法 :应用同位素标记法测定星形胶质细胞对培养液中 [3 H] D ,L 谷氨酸的摄取 ,应用四氮唑 (MTT)比色法检测星形胶质细胞的活性。结果 :MPP 15 0、2 0 0 μmol·L-1可以明显抑制星形胶质细胞摄取Glu ,抑制率达 5 8.3%和 70 .1% ,但并不影响细胞活性 ;Ⅱ组mGluRs激动剂 (2S ,2’R ,3’R) 2 (2’ ,3’ dicar boxycyclopropyl)glycine (DCG IV ) 0 .1、 1、 10 ,10 0 μmol·L-1和Ⅲ组mGluRs激动剂L( ) 2 amino 4 phosphonobutyricacid (L AP4 ) 1、10、10 0 μmol·L-1可以逆转MPP 对星形胶质细胞摄取Glu的抑制作用。结论 :MPP 抑制星形胶质细胞摄取Glu可能与直接影响谷氨酸转运体 (GluTs)的功能有关 ,激活星形胶质细胞上的Ⅱ、Ⅲ组mGluRs可以通过促进GluTs摄取Glu、进而降低细胞外液的Glu浓度而发挥神经保护作用。     

代谢型谷氨酸受体介导的电 化学信号及其生物学作用

<正>大约50年前,就已经发现谷氨酸可以诱发癫痫,并可以直接兴奋哺乳动物神经元。近20年来,药理学研究已经鉴定并克隆出不同类型的谷氨酸门控离子通道,通过激活这些通道,谷氨酸介导快速的突触后电位。20世纪80年代中期,研究者又发现谷氨酸还可以通过产生三磷酸肌醇(IP3)发挥作用,这表明存在着代谢型谷氨酸受体或非离子通道型谷氨酸受体。本文就近年代谢型谷氨酸受体(mGluRs)的结构特征、胞内信号转导机制及生物学作用综述如下。     

Ⅰ组代谢型谷氨酸受体激活调制脊髓运动神经元的下行激活

目的:探讨Ⅰ组代谢型谷氨酸受体(mGluRs)激活对离体脊髓运动神经元(MN)下行激活的调制作用.方法:应用新生大鼠(7～14 d)脊髓切片MN细胞内记录技术,记录脊髓同侧腹外侧索(iVLF)电刺激诱发的兴奋性突触后电位(EPSP,即iVLF-EPSP),观察Ⅰ组mGluRs激动剂(S)-3,5-二羟基苯基甘氨酸(DH...     

脑缺血时谷氨酸释放机制

谷氨酸是中枢神经系统主要的兴奋性神经递质,在脑缺血造成的神经元损伤过程中发挥重要作用。脑缺血时多种机制参与了谷氨酸释放的的调节,如Ca2+依赖性的出胞式释放、谷氨酸转运体调节的释放、水肿诱发的释放和受体调节的释放等。本文根据现有的文献资料,综述了脑缺血时谷氨酸释放机制。     

Metabotropic glutamate receptors modulate serotonin release in the rat periaqueductal gray matter

The role of metabotropic (mGluRs) and N-methyl-D-aspartate (NMDA) glutamate receptors on 5-hydroxytryptamine (5-HT) release has been studied in rat periaqueductal gray (PAG) matter by using in vivo microdialysis. (1S,3R)-aminocyclopentane-1,3-dicarboxylic acid [(1S,3R)-ACPD; 0.5 or 1 mM], a group I/group II mGluRs agonist, increased the dialysate 5-HT concentration. (2S)-α-ethylglutamic acid (EGlu; 1 mM), an antagonist of group II mGluRs, but not (RS)-1-aminoindan-1,5-dicarboxylic acid (AIDA; 1 mM), an antagonist of group I mGluRs, antagonized the 1S,3R-ACPD-induced effect. (S)-3,5-dihydroxyphenylglycine (DHPG; 0.5 and 1 mM), an agonist of group I mGluRs, did not modify dialysate 5-HT. (2S, 3S, 4S)-α-(carboxycyclopropyl)-glycine (L-CCG-I; 0.5 and 1 mM), an agonist of group II mGluRs, increased extracellular 5-HT. This effect was antagonized by EGlu. Similarly, L-serine-O-phosphate (L-SOP; 1 and 10 mM), an agonist of group III mGluRs, increased extracellular 5-HT and this effect was antagonized by (RS)-α-methylserine O-phosphate (M-SOP; 1 mM), an antagonist of group III mGluRs. Out of the several N-methyl-D-aspartate concentrations used (NMDA; 10, 50, 100, 500 and 1000 μM) only the 50 μM infusion significantly decreased dialysate 5-HT. The GABA_A receptor agonist, bicuculline (30 μM), increased 5-HT release on its own and antagonized the decrease caused by the opiate antagonist, naloxone (2 mM), as well as the increases caused by CCG-I or L-SOP. These data show that stimulation of PAG’s group II/group III mGluRs increases 5-HT release, while stimulation of NMDA glutamate receptors may decrease it. We speculate that glutamate does not modulate 5-HT release in the PAG directly, but via activation of tonically active GABAergic interneurons. Received: 15 January 1998 / Accepted: 22 July 1998     

Metabotropic glutamate receptors in the trafficking of ionotropic glutamate and GABA(A) receptors at central synapses

The trafficking of ionotropic glutamate (AMPA, NMDA and kainate) and GABA(A) receptors in and out of, or laterally along, the postsynaptic membrane has recently emerged as an important mechanism in the regulation of synaptic function, both under physiological and pathological conditions, such as information processing, learning and memory formation, neuronal development, and neurodegenerative diseases. Non-ionotropic glutamate receptors, primarily group I metabotropic glutamate receptors (mGluRs), co-exist with the postsynaptic ionotropic glutamate and GABA(A) receptors. The ability of mGluRs to regulate postsynaptic phosphorylation and Ca(2+) concentration, as well as their interactions with postsynaptic scaffolding/signaling proteins, makes them well suited to influence the trafficking of ionotropic glutamate and GABA(A) receptors. Recent studies have provided insights into how mGluRs may impose such an influence at central synapses, and thus how they may affect synaptic signaling and the maintenance of long-term synaptic plasticity. In this review we will discuss some of the recent progress in this area: i) long-term synaptic plasticity and the involvement of mGluRs; ii) ionotropic glutamate receptor trafficking and long-term synaptic plasticity; iii) the involvement of postsynaptic group I mGluRs in regulating ionotropic glutamate receptor trafficking; iv) involvement of postsynaptic group I mGluRs in regulating GABA(A) receptor trafficking; v) and the trafficking of postsynaptic group I mGluRs themselves.     

Metabotropic glutamate receptor-dependent long-term potentiation

The induction of the most common form of LTP is well known to involve activation of N-methyl-d-aspartate receptors. However, considerable evidence has also shown that certain forms of LTP induction at excitatory synapses onto both principle cells and interneurons are dependent on activation of metabotropic glutamate receptors (mGluRs). mGluR-dependent LTP occurs in widespread areas of the brain including the neocortex, hippocampus, striatum and nucleus accumbens. mGluR-dependent forms of LTP have been found to be diverse, involving activation of mGluR1 or mGluR5 and can be of AMPAR-mediated transmission or of NMDAR-mediated transmission. Furthermore, the mGluR-dependent LTP may involve activation of other receptors, in particular, activation of NMDAR, dopamine and adenosine receptors. mGluR-dependent LTP can be expressed presynaptically or postsynaptically, and can involve a range of intracellular mediators including protein kinase C (PKC) and protein kinase A (PKA), tyrosine kinase Src and nitric oxide (NO).     

Blockade of glutamate transporters leads to potentiation of NMDA receptor current in layer V pyramidal neurons of the rat prefrontal cortex via group II metabotropic glutamate receptor activation

Membrane currents of layer V pyramidal cells in slices of the rat prefrontal cortex (PFC) were recorded with the patch-clamp technique. In an Mg(2+)-free superfusion medium l-trans-pyrrolidine-2,4-dicarboxylic acid (PDC), a preferential blocker of astrocytic glutamate transporters, caused inward current due to the activation of NMDA receptors. The blockade of conducted action potentials by tetrodotoxin did not interfere with this effect. ATP was inactive when given alone and potentiated the NMDA-induced current in an Mg(2+)-containing but not Mg(2+)-free superfusion medium. Agonists of group I ((S)-3,5-dihydroxyphenylglycine; DHPG) and II ((1R,4R,5S,6R)-4-amino-2-oxabicyclo[3.1.0]hexane-4,6-dicarboxylic acid; LY 379268) metabotropic glutamate receptors (mGluRs) also potentiated responses to NMDA, whereas the group III mGluR agonist l-(+)-2-amino-4-phosphonobutyric acid (l-AP4) did not affect them. In contrast to ATP, PDC evoked inward current in the absence but not in the presence of external Mg(2+), when given alone, and facilitated the NMDA effect Mg(2+)-independently. The PDC-induced facilitation of NMDA responses was blocked by group II ((2S)-2-amino-2-[(1S,2S)-2-carboxycycloprop-1-yl]-3-(xanth-9-yl) propanoic acid; LY 341495), but not group I ((RS)-1-aminoindan-1,5-dicarboxylic acid; AIDA) or III (alpha-methyl-3-methyl-4-phosphonophenylglycine; UBP 1112) mGluR antagonists. In conclusion, the blockade of astrocytic glutamate uptake by PDC may lead to a stimulation of group II mGluRs, while the triggering of exocytotic glutamate release from astrocytes by ATP may cause activation of group I mGluRs, both situated postsynaptically at layer V PFC pyramidal cells. Either group of mGluRs may interact with NMDA receptors in a positive manner.     

亲代谢型谷氨酸受体和相关神经疾病

谷氨酸的过量释放在多种神经系统疾病的发生发展过程中发挥着重要作用。虽然离子型谷氨酸受体拮抗剂在动物模型中取得了一定的治疗效果,但因其同时阻断了正常的兴奋性传递,限制了这类化合物的临床应用;而mG luR s通过突触前机制抑制谷氨酸的释放,有望成为某些神经系统疾病治疗的新靶点。该文就近年来国内外mG luR s在这些神经疾病中的研究进展作一综述。     

Metabotropic glutamate receptors (mGluRs) and diabetic neuropathy

Multiple in vivo and in vitro studies show that excessive release of glutamate, and subsequent activation of ionotropic glutamate receptors (iGluRs) and some metabotropic glutamate receptors (mGluRs) cause neuronal cell death through either necrosis or apoptosis. However, recently alternative evidence has shown that mGluRs have modulatory effects on excitotoxicity and neuronal cell death. Metabotropic glutamate receptors form a family of eight subtypes (mGluR1-8), subdivided into three groups (I-III) that initiate their biological effects by G protein-linked intracellular signal transduction. Their expression throughout the mammalian nervous system implicates these receptors as essential mediators of a cell's fate during injury to the nervous system. Activation of group-II (mGluR2 and -3) or group-III metabotropic glutamate receptors (mGluR4, -6, -7 and -8) has been established to be neuroprotective in vitro and in vivo. In contrast, group-I mGluRs (mGluR1 and -5) need to be antagonized in order to evoke protection. The pathological signaling pathways associated with diabetic neuropathy are complex and this influences development of appropriate therapies. The Group II mGluRs target several signaling pathways affected in diabetic neuropathy, prevent cellular injury in the peripheral nervous system, and may provide a novel mechanism for treatment of diabetic neuropathy. Direct or indirect activation of mGluR2/3 in animal models protects against development of diabetic neuropathy. The potential mechanisms and role of mGluRs in protection against diabetic neuropathy will be reviewed.     

Constitutive endocytosis of the metabotropic glutamate receptor mGluR7 is clathrin-independent

Metabotropic glutamate receptors (mGluRs) are G protein-coupled receptors (GPCRs) that are widely expressed throughout the brain and are involved in synaptic development, transmission, and plasticity. The endocytosis of several members of the GPCR superfamily of receptors, such as beta-adrenergic receptors, has been studied extensively. In contrast, the mechanisms regulating mGluR endocytosis and intracellular trafficking remain poorly defined. We describe here for the first time a distinct endocytic and intracellular sorting pathway utilized by mGluR7. We show that mGluR7 constitutively internalizes via a non-clathrin mediated pathway in heterologous cells and in neurons. Unlike clathrin-mediated NMDAR endocytosis, mGluR7 traffics via an Arf6-positive endosomal pathway, similar to other well-characterized proteins such as major histocompatibility complex class I (MHC I) and the GPI-anchored protein CD59. Thus constitutive endocytosis of mGluR7 in neurons is not regulated by clathrin-dependent mechanisms, and this clathrin-independent pathway ultimately determines the amount of receptor present on the plasma membrane available to bind and respond to glutamate.