The Multifaceted Roles of KCC2 in Cortical Development

KCC2 is a neuron-specific chloride-extruder that shapes cortical development.Changes in the strength of GABAergic synapses brought about by up- and downregulation Cl? extrusion exert major effect on neuronal plasticity network functions.The structural interactions C terminus regulate signaling pathways involved early survival, spinogenesis, glutamatergic synaptic transmission.The recently discovered tertiary quaternary structures other cation/chloride cotransporter (CCC) members provide first insights into their functions at an atomic level.The multisite phosphorylation code controls its membrane expression stability, as well intrinsic transport rate during development, plasticity, disease.KCC2 mutations linked to epilepsy autism spectrum disorder (ASD) disrupt both ion transport-dependent -independent functions, suggesting novel molecular basis for CNS disorders related roles KCC2. KCC2, best known sets polarity currents maturation, multifunctional molecule can cytoskeletal dynamics via C-terminal domain (CTD). We describe cellular mechanisms multiple splice variants, ranging from developmental apoptosis control events formation dendritic spines. The versatility actions subcellular levels also evident mature neurons disease, aging. Thus, has emerged one most important molecules shape overall phenotype. Fast transmission relies fluxes through ligand-gated channels. Although default state cell have high intracellular chloride concentration ([Cl?]i), evolved unique ability maintain low [Cl?]i, which needed generation hyperpolarizing across GABAA glycine receptors (GABAARs GlyRs) [1.Kaila K. et al.Cation-chloride cotransporters disease.Nat. Rev. Neurosci. 2014; 15: 637-654Crossref PubMed Scopus (317) Google Scholar]. 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Physiol. 318: C225-C237Crossref coordinated five amino acids (N131, I132, Y216, P429, T432 hKCC1 Scholar]). positions sites resolved mKCC4 hKCC4 DrNKCC1 Surprisingly, two hKCC4: directly cotransport, second allosterically facilitates occupancy former. In hKCC1, main-chain amide groups G134, V135, I136, hydroxyl group S430, ion, whereas allosteric coordination center G433, I434, M435, Y589 TM10 Scholar].The N-terminal domains yield poor resolution EM, indicating conformational flexibility. Interestingly, KCC2/KCC4 ~25 acid loop blocks cytoplasmic entry translocation pore. Consistent function this modulator transporter, deletion or mutation activated transport.tWith exception monomeric showed dimeric assembly, had been predicted before. dimer interface comprises TMDs (CTDs) swapped conformation CTD subunit placed under TMD (Figure 2B). swapping occurs 'scissor helix' region connects within each subunit, shown hKCCs 130.Zhao extracellular stabilize but not hKCC2, hKCC3, dimers Scholar,132.Xie It worth pointing out here SDS-resistant higher homo-oligomers western blots are obviously result well-known aggregation proteins subjected heating acidic pH [134.Sagné al.SDS-resistant proteins: application purification vesicular monoamine transporter.Biochem. 316: 825-831Crossref (69) particular, amount oligomers SDS gels bears no relation presence functional original tissue.As whole, accumulating knowledge provides information be used modulation inhibitors (reviewed [133.Delpire Scholar]) activators [123.Gagnon M. al.Chloride enhancers therapeutics neurological diseases.Nat. 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