Michael Smith Laboratories, The University of British Columbia, 2185 East Mall, Vancouver, BC, V6T 1Z4, Canada.
The Vancouver Prostate Centre, Jack Bell Research Centre, 2660 Oak Street, Vancouver, BC, V6H 3Z6, Canada.
Sci Rep. 2023 Aug 11;13(1):13079. doi: 10.1038/s41598-023-38663-z.
The interplay between AMPA-type glutamate receptors (AMPARs) and major histocompatibility complex class I (MHC-I) proteins in regulating synaptic signaling is a crucial aspect of central nervous system (CNS) function. In this study, we investigate the significance of the cytoplasmic tail of MHC-I in synaptic signaling within the CNS and its impact on the modulation of synaptic glutamate receptor expression. Specifically, we focus on the Y321 to F substitution (Y321F) within the conserved cytoplasmic tyrosine YXXΦ motif, known for its dual role in endocytosis and cellular signaling of MHC-I. Our findings reveal that the Y321F substitution influences the expression of AMPAR subunits GluA2/3 and leads to alterations in the phosphorylation of key kinases, including Fyn, Lyn, p38, ERK1/2, JNK1/2/3, and p70 S6 kinase. These data illuminate the crucial role of MHC-I in AMPAR function and present a novel mechanism by which MHC-I integrates extracellular cues to modulate synaptic plasticity in neurons, which ultimately underpins learning and memory.
AMPA 型谷氨酸受体 (AMPARs) 和主要组织相容性复合体 I 类 (MHC-I) 蛋白在调节突触信号转导方面的相互作用是中枢神经系统 (CNS) 功能的一个关键方面。在这项研究中，我们研究了 MHC-I 胞质尾部在 CNS 内突触信号转导中的重要性及其对突触谷氨酸受体表达的调节作用。具体来说，我们专注于 MHC-I 中保守的胞质酪氨酸 YXXΦ 基序内的 Y321 到 F 取代 (Y321F)，该取代在 MHC-I 的内吞作用和细胞信号转导中具有双重作用。我们的研究结果表明，Y321F 取代会影响 AMPAR 亚基 GluA2/3 的表达，并导致关键激酶（包括 Fyn、Lyn、p38、ERK1/2、JNK1/2/3 和 p70 S6 激酶）的磷酸化发生改变。这些数据阐明了 MHC-I 在 AMPAR 功能中的关键作用，并提出了一种新的机制，即 MHC-I 整合细胞外信号来调节神经元中的突触可塑性，这最终是学习和记忆的基础。
