ROLE OF METABOTROPIC GLUTAMATE (ACPD) RECEPTORS AT THE PARALLEL FIBER-PURKINJE CELL SYNAPSE
ROLE OF METABOTROPIC GLUTAMATE (ACPD) RECEPTORS AT THE PARALLEL FIBER-PURKINJE CELL SYNAPSE
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DOI：
10.1152/jn.1992.68.4.1453
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发表时间：
1992-10-01
影响因子：
2.5
通讯作者：
MILLER, RJ
中科院分区：
文献类型：
--
作者：
GLAUM, SR;SLATER, NT;MILLER, RJ
1.通过检测活性立体异构体（1 S，3R）-1-氨基环戊烷-1，3-二羧酸[1 S，3R-ACPD（25-50 μ M）]对fura-2负载的、膜片钳的大鼠小脑浦肯野细胞的作用，研究了代谢型谷氨酸受体在小脑平行纤维（PF）-浦肯野细胞突触中的作用. 1 S，3R-ACPD的浴应用诱发直接突触后去极化，其在长时间（> 1分钟）应用药物期间容易脱敏。对1 S，3 R-ACPD的这种去极化反应与在皮质神经元中通过钾通道关闭介导的对IS，3 R-ACPD的缓慢去极化不同，因为它与膜电导的明显变化无关，并且不被外部钡阻断。同样，慢内向整流电流在1 S，3R-ACPD诱导的去极化过程中不受影响。1 S，3R-ACPD诱导的直接去极化不受N-甲基-D-天冬氨酸（NMDA）或（RS）-α-氨基-3-羟基-5-甲基-4-异恶唑丙酸红藻氨酸（AMPA）-KA兴奋性氨基酸（EAA）受体亚型的介导，因为这些受体的拮抗剂不阻断该反应. EAA拮抗剂L-2-氨基-3-膦酰基丙酸阻断IS，3R-ACPD诱导的其他类型细胞肌醇合成，对去极化反应无影响. Fura-2测定体细胞[Ca 2 +]i显示，在IS，3R-ACPD诱导的去极化过程中，[Ca 2 +]i不升高，除非细胞激发钙依赖性动作电位.除1 S，3R-ACPD引起的直接去极化外，PF诱发的兴奋性突触后电位（EPSP）的振幅也可逆地降低。无论1 S，3R-ACPD是否产生直接去极化，在所有细胞中均观察到这种效应。这种PF EPSP的降低通常先于去极化反应的开始，在长时间应用1 S，3R-ACPD期间不会脱敏，并且是可逆的。1 S，3R-ACPD对PF EPSP的可逆性降低与药物的突触后阻断作用无关，因为在IS，3R-ACPD存在下，浦肯野细胞对AMPA（一种介导EPSP的EAA受体亚型激动剂）的反应可逆性增强。一氧化氮合成促进剂硝普钠（1-3 mM）对PF EPSP的幅度或浦肯野细胞的膜特性没有影响。在使用穿孔贴片记录技术的实验中，使用装有制霉菌素和fura-2 AM的移液管以避免细胞索马体的透析，还观察到PF EPSP的可逆减少，这在某些情况下与内向电流相关，但[Ca 2 +] i. 10没有变化。结果提供了三个不同的网站的代谢型EAA激动剂IS，3R-ACPD的行动的证据：减少PF EPSP介导的突触前自身受体的激活，增强突触后的敏感性，和直接去极化行动。因此，在PF-浦肯野细胞突触的代谢型受体的激活可能在调节高频率传输期间在该突触的传输功效中发挥重要作用。
1. The role of metabotropic glutamate receptors at the parallel fiber (PF)-Purkinje cell synapse in cerebellum was studied by examining the actions of the active stereoisomer (1S,3R)-1-aminocyclopentane-1,3-dicarboxylic acid [1S,3R-ACPD (25-50 muM)] on fura-2-loaded, patch-clamped rat Purkinje cells in thin slices.2. The bath application of 1S,3R-ACPD evoked a direct post-synaptic depolarization that readily desensitized during prolonged (> 1 min) applications of the drug. This depolarizing response to 1S,3R-ACPD differed from the slow depolarization to IS,3R-ACPD observed in cortical neurons mediated via closure of potassium channels in that it was not associated with an obvious change in membrane conductance and was not blocked by external barium. Similarly, slow inward rectifier currents were not affected during the 1S,3R-ACPD-induced depolarization.3. The direct depolarization induced by 1S,3R-ACPD was not mediated by N-methyl-D-aspartate (NMDA) or (RS)-alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid kainate (AMPA)-KA excitatory amino acid (EAA) receptor subtypes, because the response was not blocked in the presence of antagonists of these receptors.4. The EAA antagonist L-2-amino-3-phosphonopropionic acid, which blocks IS,3R-ACPD-induced inositide synthesis in other cell types, had no effect on the depolarizing response.5. Fura-2 measurements of somatic [Ca2+]i revealed that [Ca2+]i was not elevated during the IS,3R-ACPD-induced depolarization unless the cell fired calcium-dependent action potentials.6. In addition to the direct depolarization induced by 1S,3R-ACPD, the amplitude of PF-evoked excitatory postsynaptic potentials (EPSPs) was profoundly and reversibly reduced. This effect was observed in all cells regardless of whether a direct depolarization was produced by 1S,3R-ACPD. This reduction of the PF EPSP generally preceded the onset of depolarizing responses, did not desensitize during prolonged applications of 1S,3R-ACPD, and was reversible.7. The reversible reduction of the PF EPSP by 1S,3R-ACPD was not related to a postsynaptic blocking action of the drug, because responses of Purkinje cells to AMPA, an agonist of the EAA receptor subtype mediating the EPSP, were reversibly potentiated in the presence of IS,3R-ACPD.8. The nitric oxide synthesis promoter sodium nitroprusside (1-3 mM) had no effect on the amplitude of PF EPSP or the membrane properties of Purkinje cells.9. In experiments using the perforated patch recording technique employing pipettes filled with nystatin and fura-2 AM to avoid dialysis of the cell soma, a reversible reduction of the PF EPSP was also observed, which was associated in some cases with an inward current, but no change in [Ca2+]i.10. The results provide evidence for three distinct sites of action of the metabotropic EAA agonist IS,3R-ACPD: a reduction of the PF EPSP mediated via activation of presynaptic autoreceptors, a potentiation of postsynaptic sensitivity, and a direct depolarizing action. Activation of metabotropic receptors at the PF-Purkinje cell synapse may thus play a significant role in modulating the efficacy of transmission at this synapse during periods of high-frequency transmission.