A Molecular Analysis of the Na⁺-Independent Cation Chloride Cotransporters

Abstract

The homologous genes encoding the electroneutral solute carrier family 12A (SLC12A) were identified more than 20 years ago, however, over the last few years, it has become clear that each of the genes within this family potentially encode for more than one cation-chloride cotransporter (CCC). Even more surprising, despite more than 30 years of functional studies and a wealth of knowledge on the activators, inhibitors, ion affinities, and kinetics of these cotransporters, we still cannot sufficiently explain why some cells express only one CCC isoform, while others express two, three, or more CCC isoforms. In 2009, Drs. Alvarez-Leefmans and Di Fulvio published an extensive in silico molecular analysis of the potential splice variants of the Na⁺-dependent cation-chloride cotransporters. In this review, we will look at the exceptionally large variety of potential splice variants within the Na⁺-independent cation-chloride cotransporter (SLC12A4-SLC12A7) genes, their initial tissue identification, and their physiological relevance.

Polarized Expression of Ion Channels and Solute Carrier Family Transporters on Heterogeneous Cultured Human Corneal Endothelial Cells

“…A1, also known as NKCC2, is an Na + /K + /2Cl − cotransporter, and A4, A5, and A6 function as Na + -independent cation-chloride cotransporters. 31 – 33 …”

Cation-chloride cotransporters in neuronal development, plasticity and disease

“…It is abundantly expressed in most mature mammalian central neurons, with very little or no expression in PNS neurons and non-neuronal cell types 2,6,53–55 . KCC2 is the only KCC isoform that is not expressed in glia 53,56,57 .…”

Loss of MicroRNA-137 Impairs the Homeostasis of Potassium in Neurons via KCC2

“…Besides its central role in hyperpolarizing inhibitory signaling based on chloride currents which are mediated by GABAor glycine-gated receptor channels, KCC2 also acts a structural protein crucially involved in the maturation and regulation of excitatory glutamatergic synapses [48][49][50][51]. KCC2 is required for neuronal maturation by rendering GABA hyperpolarizing [49,[52][53][54], and overexpression of KCC2 enhances dendritic spines in the adult nervous system in mice [55]. Therefore, we speculate that the elevated expression of KCC2 may also contribute to dysregulated synaptic plasticity and altered behaviors in MIR137 cKO mice.…”