The emerging role of kainate receptor functional dysregulation in pain

Abstract

Pain is a serious clinical challenge, and is associated with a significant reduction in quality of life and high financial costs for affected patients. Research efforts have been made to explore the etiological basis of pain to guide the future treatment of patients suffering from pain conditions. Findings from studies using KA (kainate) receptor agonist, antagonists and receptor knockout mice suggested that KA receptor dysregulation and dysfunction may govern both peripheral and central sensitization in the context of pain. Additional evidence showed that KA receptor dysfunction may disrupt the finely-tuned process of glutamic acid transmission, thereby contributing to the onset of a range of pathological contexts. In the present review, we summarized major findings in recent studies which examined the roles of KA receptor dysregulation in nociceptive transmission and in pain. This timely overview of current knowledge will help to provide a framework for future developing novel therapeutic strategies to manage pain.

Keywords: Pain; kainate receptors; modulation; neuron; plasticity.

Figure 1.

Splice variants and RNA editing of KA receptors. GluK1 extracellular NTD can be alternatively spliced to give rise to the GluK1-1 and GluK1-2 variants. The CTD exhibits four such variants (GluK1a, GluK1b, GluK1c, and GluK1d). GluK2 and GluK3 similarly exhibit CTD splice variants (GluK2a/GluK2b/GluK2c and GluK3a/GluK3b, respectively). GluK4 and GluK5 may not undergo alternative splicing. Splice variants are depicted including reported interaction sites with other proteins, post-translationally modified residues, and trafficking motifs. Color index: red: retention motif; purple: forward trafficking motif; orange: endocytosis; yellow: post-translational modification; green: residues or regions reported to interact with other proteins. Blue (dark or light) bars within schematic drawings of receptors represent either transmembrane domains or the re-entrant loop. Editing sites for GluK1 and GluK2 can undergo editing at the “Q/R” site, while GluK2 can also be edited at “I/V” and “Y/C” sites in the M1 transmembrane domain, thereby altering amino acid substitutions at critical sites within these receptor subunits.

Figure 2.

Post-translational modifications (phosphorylation) of KA receptors. A number of residues within KA receptor subunits were shown to be phosphorylated, including S846/S868/S880/S886 (PKC), S856/S868 (PKA), S859/S892/T976 (CaMKII). All of these phosphorylation is shown to directly impact the kainite-evoked currents, and is also illustrated to be related to the endocytosis of KA receptors, leading to recycling of KA receptors to the membrane or degradation. Moreover, phosphorylation uncouples KA receptors from postsynaptic density 95 (PSD-95), improving the overall lateral mobility of these receptors by freeing them from synaptic incorporation. LBD ligand binding domain, GLU glutamate, N N-terminal domain, C C-terminal domain, P phosphorylation, EC extracellular, IC intracellular.

Figure 3.

Schematic of domain organization of PSD95, GRIP, PICK1, and Netos with KA receptors. PDZ domain proteins (PSD95, GRIP and PICK1) are shown to interact with KA receptors through the PDZ domain-mediated interactions, which are necessary for the appropriate regulation of KA receptor-mediated synaptic functionality. Interactions with PSD95 enable KA receptors to recover more rapidly following receptor desensitization. Such interactions also drive KA receptor clustering, and KA receptors-PSD95 complex can additionally interact with mixed-lineage kinases 2 and 3 (MLK2 and MLK3), which drives JNK kinase activation. GRIP regulates KA receptor anchoring at synapses, and that the PICK1-targeted phosphorylation of KA receptors by PKC stabilizes GRIP binding. NETOs (NETO1/2) interact with KA receptors via their PDZ-ligand domains and CUB domains, thereby forming stable complexes with KA receptors. Netos interaction with KA receptors typically slow KA receptor deactivation kinetics, and such interactions also represents a regulator of KA receptor trafficking. EC extracellular, IC intracellular.