Signal transduction mechanisms of K⁺‐Cl⁻ cotransport regulation and relationship to disease

Abstract

The K+-Cl- cotransport (COT) regulatory pathways recently uncovered in our laboratory and their implication in disease state are reviewed. Three mechanisms of K+-Cl- COT regulation can be identified in vascular cells: (1) the Li+-sensitive pathway, (2) the platelet-derived growth factor (PDGF)-sensitive pathway and (3) the nitric oxide (NO)-dependent pathway. Ion fluxes, Western blotting, semi-quantitative RT-PCR, immunofluorescence and confocal microscopy were used. Li+, used in the treatment of manic depression, stimulates volume-sensitive K+-Cl- COT of low K+ sheep red blood cells at cellular concentrations <1 mM and inhibits at >3 mM, causes cell swelling, and appears to regulate K+-Cl- COT through a protein kinase C-dependent pathway. PDGF, a potent serum mitogen for vascular smooth muscle cells (VSMCs), regulates membrane transport and is involved in atherosclerosis. PDGF stimulates VSM K+-Cl- COT in a time- and concentration-dependent manner, both acutely and chronically, through the PDGF receptor. The acute effect occurs at the post-translational level whereas the chronic effect may involve regulation through gene expression. Regulation by PDGF involves the signalling molecules phosphoinositides 3-kinase and protein phosphatase-1. Finally, the NO/cGMP/protein kinase G pathway, involved in vasodilation and hence cardiovascular disease, regulates K+-Cl- COT in VSMCs at the mRNA expression and transport levels. A complex and diverse array of mechanisms and effectors regulate K+-Cl- COT and thus cell volume homeostasis, setting the stage for abnormalities at the genetic and/or regulatory level thus effecting or being affected by various pathological conditions.

Functional and molecular characterization of multiple K–Cl cotransporter isoforms in corneal epithelial cells

“…The more rapid RVD response by HCEC than in RCEC, could be attributed to higher KCC1 expression levels. These results validate that-as in many other cell types (Adragna et al, 2006;Adragna et al, 2004;Gillen et al, 1996;Ubels et al, 2006)-KCC1 is the "house-keeping" isoform, involved in maintenance of steady-state ionic homeostasis as well as CEC volume regulation.…”

“…NEM selectively stimulates KCC in multiple cell systems (Adragna et al, 2004) and may be used as a diagnostic tool to detect the functional presence of KCC as well as hypotonicity-induced cell swelling. Four isoforms of KCC (KCC1-4) have been identified (see review by Adragna et al (Adragna et al, 2006)). KCC1 is an ubiquitously expressed "house-keeping" transporter involved in maintenance of cell volume and ionic homeostasis (Adragna et al, 2006;Gillen et al, 1996).…”

“…Four isoforms of KCC (KCC1-4) have been identified (see review by Adragna et al (Adragna et al, 2006)). KCC1 is an ubiquitously expressed "house-keeping" transporter involved in maintenance of cell volume and ionic homeostasis (Adragna et al, 2006;Gillen et al, 1996). Neuron-specific KCC2 is present in the retina and central nervous system, where it plays a crucial role in maintaining low intracellular Cl − and GABAergic synaptic inhibition Rivera et al, 1999;Vardi et al, 2000;Vu et al, 2000).…”

Arachidonic Acid Mediates Apoptosis Induced by N-Ethylmaleimide in HepG2 Human Hepatoblastoma Cells

“…Therefore, KCC has been implicated not only in regulatory volume decrease (Lauf et al, 1992), but also in transepithelial salt absorption (Amlal et al, 1994), myocardial K ＋ loss during ischemia (Yan et al, 1996), blood pressure control (Adragna et al, 2006), regulation of neuronal Cl − concentration (Rivera et al, 1999), and renal K ＋ secretion (Ellison et al, 1985). Interestingly, recent reports have suggested that KCC is expressed in a variety of human cancer cells.…”

Arachidonic Acid Activates K+-Cl--cotransport in HepG2 Human Hepatoblastoma Cells

“…KCC has been implicated not only in regulatory volume decrease (Lauf et al, 1992), but also in transepithelial salt absorption (Amlal et al, 1994), myocardial K ＋ loss during ischemia (Yan et al, 1996), blood pressure control (Adragna et al, 2006), regulation of neuronal Cl − concentration (Rivera et al, 1999), and renal K ＋ secretion (Ellison et al, 1985). Interestingly, recent reports have suggested that KCC is expressed in a variety of human cancer cells.…”