Human and Murine Phenotypes Associated with Defects in Cation-Chloride Cotransport

Abstract

The diuretic-sensitive cotransport of cations with chloride is mediated by the cation-chloride cotransporters, a large gene family encompassing a total of seven Na-Cl, Na-K-2Cl, and K-Cl cotransporters, in addition to two related transporters of unknown function. The cation-chloride cotransporters perform a wide variety of physiological roles and differ dramatically in patterns of tissue expression and cellular localization. The renal-specific Na-Cl cotransporter (NCC) and Na-K-2Cl cotransporter (NKCC2) are involved in Gitelman and Bartter syndrome, respectively, autosomal recessive forms of metabolic alkalosis. The associated phenotypes due to loss-of-function mutations in NCC and NKCC2 are consistent, in part, with their functional roles in the distal convoluted tubule and thick ascending limb, respectively. Other cation-chloride cotransporters are positional candidates for Mendelian human disorders, and the K-Cl cotransporter KCC3, in particular, may be involved in degenerative peripheral neuropathies linked to chromosome 15q14. The characterization of mice with both spontaneous and targeted mutations of several cation-chloride cotransporters has also yielded significant insight into the physiological and pathophysiological roles of several members of the gene family. These studies implicate the Na-K-2Cl cotransporter NKCC1 in hearing, salivation, pain perception, spermatogenesis, and the control of extracellular fluid volume. Targeted deletion of the neuronal-specific K-Cl cotransporter KCC2 generates mice with a profound seizure disorder and confirms the central role of this transporter in modulating neuronal excitability. Finally, the comparison of human and murine phenotypes associated with loss-of-function mutations in cation-chloride cotransporters indicates important differences in physiology of the two species and provides an important opportunity for detailed physiological and morphological analysis of the tissues involved.

WNK1 and OSR1 regulate the Na + , K + , 2Cl − cotransporter in HeLa cells

“…NKCC1 is expressed in secretory epithelia, including trachea, salivary glands, and inner ear. In these tissues, it is localized in the basolateral membrane and takes up ions to support chloride secretion by apical chloride channels into the lumen of these tissues (27,28). NKCC1 is ubiquitously expressed in nonepithelial tissues, such as cardiac cells and fibroblasts, and influences volume regulation and ion balance through its sensitivity to changes in osmotic stress, intracellular chloride, and, directly or indirectly, cell volume.…”

Functional Analysis of a Potassium-Chloride Co-Transporter 3 (SLC12A6) Promoter Polymorphism Leading to an Additional DNA Methylation Site

“…As it has been proposed that SLC12A6 resembles a positional candidate gene for bipolar disorder and subtypes of schizophrenia (Delpire and Mount, 2002;Meyer et al, 2005), we investigated whether the SLC12A6 polymorphic promoter sites are prone to stimulation by common mood stabilizers, such as Li and valproic acid, which are both commonly used in the treatment of bipolar disorder, and the antipsychotic drug haloperidol, frequently used in the treatment of psychoses. However, presence of haloperidol, valproic acid, or Li had no effect on reporter gene expression in our test system, as they also had no influence on promoter methylation (data not shown).…”

A Concerted Role of Na+—K+—Cl− Cotransporter and Na+/Ca2+ Exchanger in Ischemic Damage

“…Na + -K + -Cl À cotransporter isoform 1 (NKCC1) has a broad tissue distribution, whereas NKCC2 is found only in the vertebrate kidney (Delpire and Mount, 2002). NKCC serves multiple functions, including ion and fluid movements in secreting or reabsorbing epithelia and cell volume regulation (Delpire and Mount, 2002;Russell, 2000). We reported that NKCC1 activity, reflected by protein phosphorylation, is increased in the cortex and striatum during 0 to 8 h reperfusion after 2-h transient middle cerebral artery occlusion in rat (tMCAO, Yan et al, 2003).…”