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.

• Authors: N C Adragna, C M Ferrell, J Zhang, M Di Fulvio, C F Temprana, A Sharma, R E W Fyffe, D R Cool, P K Lauf
• Journal: Acta physiologica (Oxford, England) (Acta Physiol (Oxf)) 2006 May-Jun Vol. 187 Issue 1-2 Pg. 125-39 ISSN: 1748-1708 [Print] England
• PMID: 16734749 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Review)

Chemical References

• Platelet-Derived Growth Factor
• Symporters
• potassium-chloride symporters

Topics

• Atherosclerosis (metabolism)
• Cardiovascular Diseases (metabolism)
• Cell Size
• Gene Expression Regulation
• Humans
• Ion Transport
• Muscle, Smooth, Vascular (metabolism, pathology)
• Platelet-Derived Growth Factor (metabolism)
• Signal Transduction (physiology)
• Symporters (genetics, metabolism)
• Vasodilation (physiology)