Signal transduction mechanisms of K+-Cl− cotransport regulation and relationship to disease
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 mmand 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.
Keywords: K-Cl cotransport; lithium; nitric oxide pathway; platelet-derived growth factor; potassium-chloride cotransporter 1 protein; potassium-chloride cotransporter mRNA expression; signal transduction; vascular cells
Document Type: Research Article
Affiliations: 1: Department of Pharmacology & Toxicology, Wright State University School of Medicine, Dayton, OH, USA 2: Department of Neuroscience, Cell Biology & Physiology, Wright State University School of Medicine, Dayton, OH, USA
Publication date: May 1, 2006