Qneibi Mohammad, Bdir Sosana, Bdair Mohammad, Aldwaik Samia Ammar, Heeh Maram, Sandouka Dana, Idais Tala
Department of Biomedical Sciences, Faculty of Medicine and Health Sciences, An-Najah National University, Nablus, Palestine.
Neuro-Pal Center, Birzeit, Palestine.
FEBS J. 2025 May;292(10):2433-2478. doi: 10.1111/febs.17287. Epub 2024 Oct 11.
α-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) ionotropic glutamate receptors (AMPARs) mediate rapid excitatory synaptic transmission in the mammalian brain, primarily driven by the neurotransmitter glutamate. The modulation of AMPAR activity, particularly calcium-permeable AMPARs (CP-AMPARs), is crucially influenced by various auxiliary subunits. These subunits are integral membrane proteins that bind to the receptor's core and modify its functional properties, including ion channel kinetics and receptor trafficking. This review comprehensively catalogs all known AMPAR auxiliary proteins, providing vital insights into the biochemical mechanisms governing synaptic modulation and the specific impact of CP-AMPARs compared to their calcium-impermeable AMPA receptor (CI-AMPARs). Understanding the complex interplay between AMPARs and their auxiliary subunits in different brain regions is essential for elucidating their roles in cognitive functions such as learning and memory. Importantly, alterations in these auxiliary proteins' expression, function or interactions have been implicated in various neurological disorders. Aberrant signaling through CP-AMPARs, in particular, is associated with severe synaptic dysfunctions across neurodevelopmental, neurodegenerative and psychiatric conditions. Targeting the distinct properties of AMPAR-auxiliary subunit complexes, especially those involving CP-AMPARs, could disclose new therapeutic strategies, potentially allowing for more precise interventions in treating complex neuronal disorders.
α-氨基-3-羟基-5-甲基-4-异恶唑丙酸（AMPA）离子型谷氨酸受体（AMPARs）介导哺乳动物大脑中的快速兴奋性突触传递，主要由神经递质谷氨酸驱动。AMPAR活性的调节，尤其是钙通透型AMPARs（CP-AMPARs），受到多种辅助亚基的关键影响。这些亚基是整合膜蛋白，与受体核心结合并改变其功能特性，包括离子通道动力学和受体运输。本综述全面编目了所有已知的AMPAR辅助蛋白，深入洞察了控制突触调节的生化机制以及CP-AMPARs与其钙不通透型AMPA受体（CI-AMPARs）相比的具体影响。了解不同脑区中AMPARs与其辅助亚基之间的复杂相互作用对于阐明它们在学习和记忆等认知功能中的作用至关重要。重要的是，这些辅助蛋白的表达、功能或相互作用的改变与各种神经系统疾病有关。特别是，通过CP-AMPARs的异常信号传导与神经发育、神经退行性和精神疾病中的严重突触功能障碍有关。针对AMPAR-辅助亚基复合物的独特特性，尤其是那些涉及CP-AMPARs的特性，可能会揭示新的治疗策略，有可能在治疗复杂的神经元疾病时实现更精确的干预。
