Shin J H, Kim Y S, Worley P F, Linden D J
Department of Neuroscience, The Johns Hopkins University School of Medicine, 725 North Wolfe Street, Baltimore, MD 21205, USA.
Neuroscience. 2009 Sep 1;162(3):688-93. doi: 10.1016/j.neuroscience.2009.01.044. Epub 2009 Jan 29.
Activation of cerebellar Purkinje cells by either brief depolarizing steps or bursts of climbing fiber synaptic activation evokes a slow inward current, which we have previously called depolarization-induced slow current or DISC. DISC is triggered by Ca influx via voltage-sensitive Ca channels and is attenuated by inhibitors of vacuolar ATPase or vesicle fusion. This led us to suggest that DISC required vesicular release of glutamate from the somatodendritic region of Purkinje cells. Furthermore, we found that DISC was attenuated by the mGluR1 antagonist 7-(hydroxyimino)cyclopropa[b]chromen-1a-carboxylate ethyl ester (CPCCOEt), indicating that DISC required autocrine activation of metabotropic glutamate receptor 1 (mGluR1). Here, we have revisited the role of mGluR1 and found that it is, in fact, not required for DISC. CPCCOEt, but not three other specific mGluR1 antagonists (JNJ16259685, alpha-amino-5-carboxy-3-methyl-2-thiopheneacetic acid (3-MATIDA), Bay 36-7620), attenuated DISC, even though all four of these drugs produced near-complete blockade of current evoked by puffs of the exogenous mGluR1/5 agonist DHPG. Cerebellar slices derived from mGluR1 null mice showed substantial DISC that was still attenuated by CPCCOEt. mGluR5 is functionally similar to mGluR1, but is not expressed at high levels in cerebellar Purkinje cells. 2-Methyl-6-(phenylethynyl)pyridine hydrochloride (MPEP), an mGluR5 antagonist, did not attenuate DISC, and DISC was still present in Purkinje cells derived from mGluR1/mGluR5 double null mice. Thus, neither mGluR1 nor mGluR5 is required for DISC in cerebellar Purkinje cells.
短暂的去极化步骤或攀爬纤维突触激活爆发均可激活小脑浦肯野细胞，从而诱发一种缓慢的内向电流，我们之前将其称为去极化诱导慢电流（DISC）。DISC由通过电压敏感性钙通道的钙内流触发，并被液泡ATP酶抑制剂或囊泡融合抑制剂减弱。这使我们推测DISC需要浦肯野细胞体树突区域囊泡释放谷氨酸。此外，我们发现DISC被代谢型谷氨酸受体1（mGluR1）拮抗剂7-（羟基亚氨基）环丙[b]色烯-1a-羧酸乙酯（CPCCOEt）减弱，表明DISC需要mGluR1的自分泌激活。在此，我们重新审视了mGluR1的作用，发现实际上DISC并不需要它。CPCCOEt可减弱DISC，但其他三种特异性mGluR1拮抗剂（JNJ16259685、α-氨基-5-羧基-3-甲基-2-噻吩乙酸（3-MATIDA）、Bay 36-7620）则不能，尽管这四种药物均对外源性mGluR1/5激动剂二羟基苯基甘氨酸（DHPG） puff诱发的电流产生近乎完全的阻断。来自mGluR1基因敲除小鼠的小脑切片显示出大量的DISC，且仍被CPCCOEt减弱。mGluR5在功能上与mGluR1相似，但在小脑浦肯野细胞中不高表达。mGluR5拮抗剂盐酸2-甲基-6-（苯乙炔基）吡啶（MPEP）不会减弱DISC，并且在来自mGluR1/mGluR5双基因敲除小鼠的浦肯野细胞中仍存在DISC。因此，小脑浦肯野细胞中的DISC既不需要mGluR1也不需要mGluR5。
