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. 2023 Nov 11;59:431–438. doi: 10.1016/j.jdsr.2023.11.001

Fig. 2.

Fig. 2

Summary of the KCC2 regulation. KCC2 is regulated by many factors. Factors that would up-regulate the KCC2 expression are presented in green, while factors that would down-regulate it are presented in yellow. Stress induces inflammation, while inflammation down-regulates KCC2. KCC2 is up-regulated when piperine binds to TRPV1, the capsaicin receptor. OXT, which is a neuropeptide, binds to both OXTR and RAGE. When OXT binds to these receptors, GSK3β is inactivated. Because GSK3β up-regulates IL-1β, OXT down-regulates inflammation and results in KCC2 downregulation. KKT is one of the Kampo medicines prescribed to patients presenting symptoms of anxiety, depression, and insomnia. KKT up-regulates OXT which results in the upregulation of KCC2. RAGE acts as a receptor not only for OXT but also for P. g LPS. When P. g LPS binds to RAGE, GSK3β is activated. RAGE activates TLR4, which also acts as the P. g LPS receptor. Moreover, TLR4 activates IL-1β and WNK-SPAK which leads to GSK3β activation. KSS inhibits RAGE, while BIO inhibits GSK3β. FLT3 and TrkB are receptor tyrosine kinases. As ligands, FLT3L binds to FLT3 and BDNF binds to TrkB. When these ligands bind to receptors, PI3K is activated. The PI3K activates AKT and up-regulates GSK3β. Akt has been reported to phosphorylate CREB and regulate BDNF. CREB is down-regulated by miR-134 post-translationally. MiR-134 is down-regulated by SIRT1, which is a histone deacetylase, and its activation is known to extend lifespan of yeast to human. SIRT1 is activated by resveratrol. Activated SIRT1 inhibits REST expression by binding to the transcriptional regulatory region of REST genes. REST translocates into the nucleus together with MECP2 via GSK3β and inhibits KCC2 expression. GSK3β inhibits mitochondrial activity, while mitochondrial dysfunction decreases KCC2 expression. Mitochondrial activity is regulated by not only GSK3β but also SIRT1 or miR-137. Please refer to the text for details. KCC2, K+-Cl- co-transporter 2; TRPV1, transient receptor potential cation channel subfamily V Member 1; OXT, oxytocin; OXTR, OXT receptor; RAGE, receptors for advanced glycation end products; GSK3β, glycogen synthase kinase 3β; IL-1β, nterleukin-1 beta; KKT, Kamikihito; P. g LPS, LPS derived from Porphyromonas gingivalis; TLR4, Toll-like receptor 4; WNK, with-no-lysine kinase; SPAK, STE20/SPS1-related proline/alanine-rich kinase; KSS, Kamishoyosan; BIO, 6-bromoindirubin-3'-oxime/ GSK-3 Inhibitor IX; FLT3, fms-like tyrosine kinase 3; FLT3L, FLT3 ligand; TrkB, tropomyosin receptor kinase B; BDNF, brain-derived neurotrophic factor; PI3K, phosphatidylinositol-3 kinase; CREB, cAMP response element binding protein; SIRT1, sirtuin 1; REST, RE1-silencing transcription factor; MECP2, methyl-CpG–binding protein 2.