da Silva José Afonso Corrêa, Schröder Nadja
Department of Physiology, Institute for Basic Health Sciences, Federal University of Rio Grande do Sul, Porto Alegre, Brazil.
National Institute of Science and Technology for Translational Medicine (INCT-TM), Conselho Nacional de Desenvolvimento Cientifico e Tecnológico (CNPq), Brasília, Brazil.
CNS Neurol Disord Drug Targets. 2023;22(5):624-633. doi: 10.2174/1871527321666220510141735.
It is believed that degenerative conditions that give rise to neurological diseases may share an abnormal influx of Ca, mainly through glutamate receptors. Current research on the glutamatergic system indicates that the N-methyl-D-aspartate receptor (NMDAR) is not the only receptor permeable to Ca. Under certain conditions, α -amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (AMPARs) are able to rapidly and potently mediate a neurotoxic Ca influx. AMPARs are encoded by four genes designated GluR 1-4. The presence of the edited GluA2 subunit makes the heteromeric AMPAR impermeable to Ca (CI-AMPAR's). On the other hand, the lack of GluA2 or disruptions in its post-translational editing result in Ca-permeable AMPA receptors (CP-AMPARs). In addition to triggering behavioral changes, the increase in CP-AMPARs is documented in several neurodegenerative, neuroinflammatory and neurotoxic conditions, demonstrating that AMPAR changes may play a role in the emergence and evolution of pathological conditions of the central nervous system (CNS). Seeking to better understand how CP-AMPARs influence CNS neuropathology, and how it may serve as a pharmacological target for future molecules, in this article, we summarize and discuss studies investigating changes in the composition of AMPARs and their cellular and molecular effects, to improve the understanding of the therapeutic potential of the CP-AMPAR in neurodegenerative, neurotoxic and neuroinflammatory diseases.
人们认为，引发神经疾病的退行性疾病可能存在异常的钙内流，主要是通过谷氨酸受体。目前对谷氨酸能系统的研究表明，N-甲基-D-天冬氨酸受体（NMDAR）并非唯一可通透钙的受体。在某些情况下，α-氨基-3-羟基-5-甲基-4-异恶唑丙酸受体（AMPARs）能够快速且有力地介导神经毒性钙内流。AMPARs由名为GluR 1 - 4的四个基因编码。编辑后的GluA2亚基的存在使异聚体AMPAR对钙不通透（CI-AMPARs）。另一方面，GluA2的缺失或其翻译后编辑的破坏会导致钙通透型AMPA受体（CP-AMPARs）的产生。除了引发行为变化外，CP-AMPARs的增加在几种神经退行性、神经炎症和神经毒性疾病中都有记录，这表明AMPAR的变化可能在中枢神经系统（CNS）病理状况的出现和演变中起作用。为了更好地理解CP-AMPARs如何影响中枢神经系统神经病理学，以及它如何作为未来分子的药理学靶点，在本文中，我们总结并讨论了研究AMPARs组成变化及其细胞和分子效应的研究，以增进对CP-AMPAR在神经退行性、神经毒性和神经炎症性疾病中治疗潜力的理解。
