Abstract
Cation chloride cotransporters (CCC) play an essential role for neuronal chloride homeostasis. K+-Cl− cotransporter (KCC2), is the principal Cl−-extruder, whereas Na+-K+-Cl− cotransporter (NKCC1), is the major Cl−-uptake mechanism in many neurons. As a consequence, the action of the inhibitory neurotransmitters gamma-aminobutyric acid (GABA) and glycine strongly depend on the activity of these two transporters. Knowledge of the mechanisms involved in ion transport and regulation is thus of great importance to better understand normal and disturbed brain function. Although no overall 3-dimensional crystal structures are yet available, recent molecular and phylogenetic studies and modeling have provided new and exciting insights into structure-function relationships of CCC. Here, we will summarize our current knowledge of the gross structural organization of the proteins, their functional domains, ion binding and translocation sites, and the established role of individual amino acids (aa). A major focus will be laid on the delineation of shared and distinct organizational principles between KCC2 and NKCC1. Exploiting the richness of recently generated genome data across the tree of life, we will also explore the molecular evolution of these features.
Highlights
The solute carrier 12 (SLC12) gene family encodes electroneutral, secondary active cation-chloride cotransporters (CCCs)
A major focus will be laid on the delineation of shared and distinct organizational principles between KCC2 and NKCC1
Additional whole genome duplication (2R hypothesis) and independent gene duplication events at the base of vertebrates led to their subfunctionalization into paralogs K+-Cl− cotransporter (KCC) (KCC1–4), Na+-K+-Cl− cotransporter (NKCC) (NKCC1+2) and Na+-Cl− inward cotransporters (NCCs), NCC2
Summary
Edited by: Igor Medina, Institut de Neurobiologie de la Méditerranée (INMED)/INSERM U-901, France. Cation chloride cotransporters (CCC) play an essential role for neuronal chloride homeostasis. K+-Cl− cotransporter (KCC2), is the principal Cl−-extruder, whereas Na+K+-Cl− cotransporter (NKCC1), is the major Cl−-uptake mechanism in many neurons. Knowledge of the mechanisms involved in ion transport and regulation is of great importance to better understand normal and disturbed brain function. No overall 3-dimensional crystal structures are yet available, recent molecular and phylogenetic studies and modeling have provided new and exciting insights into structure-function relationships of CCC. We will summarize our current knowledge of the gross structural organization of the proteins, their functional domains, ion binding and translocation sites, and the established role of individual amino acids (aa). A major focus will be laid on the delineation of shared and distinct organizational principles between KCC2 and NKCC1.
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