Tyrosine phosphorylation of glutamate receptors by non-receptor tyrosine kinases: roles in depression-like behavior

Abstract

Several key members of the non-receptor tyrosine kinase (nRTK) family are abundantly present within excitatory synapses in the mammalian brain. These neuron-enriched nRTKs interact with glutamate receptors and phosphorylate the receptors at tyrosine sites. The N-methyl-D-aspartate receptor is a direct substrate of nRTKs and has been extensively investigated in its phosphorylation responses to nRTKs. The -amino-3-hydroxy-5-methylisoxazole-4-propionic acid receptor is the other glutamate receptor subtype that is subject to nRTK-mediated tyrosine phosphorylation. Recently, group I metabotropic glutamate receptors (mGluR1/5) were found to be sensitive to nRTKs. Robust tyrosine phosphorylation may occur in C-terminal tails of mGluR5. Tyrosine phosphorylation of glutamate receptors is either constitutive or induced activity-dependently by changing cellular and/or synaptic input. Through inducing tyrosine phosphorylation, nRTKs regulate trafficking, subcellular distribution, and function of modified receptors. Available data show that nRTK-glutamate receptor interactions and tyrosine phosphorylation of the receptors undergo drastic adaptations in mood disorders such as major depressive disorder. The remodeling of the nRTK-glutamate receptor interplay contributes to the long-lasting pathophysiology and symptomology of depression. This review summarizes the recent progress in tyrosine phosphorylation of glutamate receptors and analyzes the role of nRTKs in regulating glutamate receptors and depression-like behavior.

Regulation of Src family kinases by muscarinic acetylcholine receptors in heterologous cells and neurons

“…Ionotropic and metabotropic glutamate receptors have been identified to be biochemical substrates of Src/Fyn ( Groveman et al, 2012 ; Mao and Wang, 2016b ; Jin et al, 2017 ). SFKs bind to the intracellular domain of glutamate receptors and phosphorylate these receptors at specific residues to regulate trafficking, subcellular and subsynaptic distribution, and functions of modified receptors.…”

Insights on the Functional Interaction between Group 1 Metabotropic Glutamate Receptors (mGluRI) and ErbB Receptors

“…Despite accurate tyrosine phosphorylation sites on mGluR1 and mGluR5 have yet to be mapped in detail, the contribution of distinct TKs in mGluRI phosphorylation is emerging, along with the appreciation of their important roles in the regulation of mGluRI functions [39] (Figure 2). TKs can be primarily classified in a) non-receptor TKs, which are intracellular diffusible kinases, like the prototypical Src family, that include nine members: Src, Yes, Fyn, and Fgr, forming the SrcA subfamily, Lck, Hck, Blk, and Lyn in the SrcB subfamily, and Frk in its own subfamily, and b) receptor TKs (RTKs), subdivided in 20 subfamilies, which comprise receptors of growth factors and hormones, like nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), insulin, epidermal growth factor (EGF), and neuregulins (NRGs) [40].…”

“…Additional insights on the functional relevance of the TKs-dependent phosphorylation of mGluRI arose following functional studies with more selective drugs, that specifically target subclasses and/or single TKs, as well as through the investigation of phosphorylated tyrosine sites on mGluR1 and mGluR5 intracellular domains, serving as TKs interacting sites. Various non-receptor TKs are expressed in neurons of mammalian brain, with some proteins, like members of Src family kinase, like Src and Fyn, being particularly expressed at synaptic sites, and thus more studied for potential roles in the regulation of synaptic activity and plasticity [39]. It has been reported that Src contributes to the regulation of mGluR1 signaling and function.…”