Hellmer Chase B, Clemons Melissa Rampino, Nawy Scott, Ichinose Tomomi
Department of Ophthalmology, Visual and Anatomical Sciences, Wayne State University School of Medicine, Detroit, Michigan, 48201.
Dominic P Purpura Dept. of Neuroscience, Albert Einstein College of Medicine Bronx, Bronx, New York, 10461.
Physiol Rep. 2018 Oct;6(20):e13885. doi: 10.14814/phy2.13885.
The canonical mGluR6-Trpm1 pathway that generates the sign-inverting signal between photoreceptors and ON bipolar cells has been well described. However, one type of ON bipolar cell, the rod bipolar cell (RBC), additionally is thought to express the group I mGluRs whose function is unknown. We examined the role of group I mGluRs in mouse RBCs and here provide evidence that it controls synaptic gain between rods and RBCs. In dark-adapted conditions, the mGluR1 antagonists LY367385 and (RS)-1-Aminoindan-1,5-dicarboxylic acid, but not the mGluR5 antagonist 2-Methyl-6-(phenylethynyl)pyridine hydrochloride reduced the light-evoked responses in RBCs indicating that mGluR1, but not mGluR5, serves to potentiate RBC responses. Perturbing the downstream phospholipase C (PLC)-protein kinase C (PKC) pathway by inhibiting PLC, tightly buffering intracellular Ca , or preventing its release from intracellular stores reduced the synaptic potentiation by mGluR1. The effect of mGluR1 activation was dependent upon adaptation state, strongly increasing the synaptic gain in dark-, but not in light-adapted retinas, or in the presence of a moderate background light, consistent with the idea that mGluR1 activation requires light-dependent glutamate release from rods. Moreover, immunostaining revealed that protein kinase Cα (PKCα) is more strongly expressed in RBC dendrites in dark-adapted conditions, revealing an additional mechanism behind the loss of mGluR1 potentiation. In light-adapted conditions, exogenous activation of mGluR1 with the agonist 3,5-Dihydroxyphenylglycine increased the mGluR6 currents in some RBCs and decreased it in others, suggesting an additional action of mGluR1 that is unmasked in the light-adapted state. Elevating intracellular free Ca , consistently resulted in a decrease in synaptic gain. Our results provide evidence that mGluR1 controls the synaptic gain in RBCs.
在光感受器和ON双极细胞之间产生信号反转信号的典型mGluR6-Trpm1通路已得到充分描述。然而，一种类型的ON双极细胞，即视杆双极细胞（RBC），另外还被认为表达I组代谢型谷氨酸受体（mGluRs），其功能尚不清楚。我们研究了I组mGluRs在小鼠RBC中的作用，并在此提供证据表明它控制视杆细胞和RBC之间的突触增益。在暗适应条件下，mGluR1拮抗剂LY367385和（RS）-1-氨基茚满-1,5-二羧酸，但不是mGluR5拮抗剂盐酸2-甲基-6-（苯乙炔基）吡啶，降低了RBC中的光诱发反应，表明是mGluR1而非mGluR5增强了RBC反应。通过抑制磷脂酶C（PLC）、紧密缓冲细胞内Ca 或阻止其从细胞内储存释放来干扰下游PLC-蛋白激酶C（PKC）通路，降低了mGluR1的突触增强作用。mGluR1激活的作用取决于适应状态，在暗适应的视网膜中强烈增加突触增益，但在光适应的视网膜中或在适度背景光存在的情况下则不然，这与mGluR1激活需要视杆细胞依赖光的谷氨酸释放的观点一致。此外，免疫染色显示，在暗适应条件下，蛋白激酶Cα（PKCα）在RBC树突中的表达更强，揭示了mGluR1增强作用丧失背后的另一种机制。在光适应条件下，用激动剂3,5-二羟基苯甘氨酸对外源性mGluR1的激活在一些RBC中增加了mGluR6电流，而在另一些RBC中则降低了mGluR6电流，这表明mGluR1在光适应状态下有额外的作用。升高细胞内游离Ca 始终导致突触增益降低。我们的结果提供了mGluR1控制RBC中突触增益的证据。
