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多巴胺通过 D 受体介导的 Csk 激活、Src 抑制和减少 GluN2B 磷酸化，促进视网膜 NMDA 受体功能低下。

Dopamine promotes NMDA receptor hypofunction in the retina through D receptor-mediated Csk activation, Src inhibition and decrease of GluN2B phosphorylation.

机构信息

Instituto de Investigação e Inovação em Saúde (i3S) and Instituto de Biologia Molecular e Celular (IBMC), Universidade do Porto, Porto, Portugal.

Program of Neurosciences, Fluminense Federal University, Niterói, Brazil.

出版信息

Sci Rep. 2017 Jan 18;7:40912. doi: 10.1038/srep40912.

DOI:10.1038/srep40912
PMID:28098256
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC5241882/
Abstract

Dopamine and glutamate are critical neurotransmitters involved in light-induced synaptic activity in the retina. In brain neurons, dopamine D receptors (DRs) and the cytosolic protein tyrosine kinase Src can, independently, modulate the behavior of NMDA-type glutamate receptors (NMDARs). Here we studied the interplay between DRs, Src and NMDARs in retinal neurons. We reveal that dopamine-mediated DR stimulation provoked NMDAR hypofunction in retinal neurons by attenuating NMDA-gated currents, by preventing NMDA-elicited calcium mobilization and by decreasing the phosphorylation of NMDAR subunit GluN2B. This dopamine effect was dependent on upregulation of the canonical DR/adenylyl cyclase/cAMP/PKA pathway, of PKA-induced activation of C-terminal Src kinase (Csk) and of Src inhibition. Accordingly, knocking down Csk or overexpressing a Csk phosphoresistant Src mutant abrogated the dopamine-induced NMDAR hypofunction. Overall, the interplay between dopamine and NMDAR hypofunction, through the DR/Csk/Src/GluN2B pathway, might impact on light-regulated synaptic activity in retinal neurons.

摘要

多巴胺和谷氨酸是参与视网膜光诱导突触活动的关键神经递质。在脑神经元中，多巴胺 D 受体 (DRs) 和细胞质蛋白酪氨酸激酶Src 可以独立调节 NMDA 型谷氨酸受体 (NMDARs) 的行为。在这里，我们研究了 DRs、Src 和 NMDARs 在视网膜神经元中的相互作用。我们揭示多巴胺介导的 DR 刺激通过减弱 NMDA 门控电流、阻止 NMDA 引发的钙动员以及减少 NMDAR 亚基 GluN2B 的磷酸化来引起视网膜神经元中 NMDAR 功能低下。这种多巴胺作用依赖于经典的 DR/腺苷酸环化酶/cAMP/PKA 途径的上调、PKA 诱导的 C 末端Src 激酶 (Csk) 的激活和 Src 的抑制。因此，敲低 Csk 或过表达 Csk 磷酸化抗性Src 突变体可消除多巴胺诱导的 NMDAR 功能低下。总的来说，通过 DR/Csk/Src/GluN2B 途径，多巴胺和 NMDAR 功能低下之间的相互作用可能会影响视网膜神经元中光调节的突触活动。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/27ef/5241882/6d23ed8fe478/srep40912-f5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/27ef/5241882/3992a856d4cc/srep40912-f1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/27ef/5241882/126672f429b5/srep40912-f2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/27ef/5241882/867e66ba94ae/srep40912-f3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/27ef/5241882/1680fa25c7e6/srep40912-f4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/27ef/5241882/6d23ed8fe478/srep40912-f5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/27ef/5241882/3992a856d4cc/srep40912-f1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/27ef/5241882/126672f429b5/srep40912-f2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/27ef/5241882/867e66ba94ae/srep40912-f3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/27ef/5241882/1680fa25c7e6/srep40912-f4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/27ef/5241882/6d23ed8fe478/srep40912-f5.jpg

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