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 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.
Adragna
N C
NC
Cell Biophysics Group, Wright State University School of Medicine, Dayton, OH 45435, USA. norma.adragna@wright.edu
Ferrell
C M
CM
Zhang
J
J
Di Fulvio
M
M
Temprana
C F
CF
Sharma
A
A
Fyffe
R E W
RE
Cool
D R
DR
Lauf
P K
PK
D050197:Atherosclerosis / Q000378:metabolism*; D002318:Cardiovascular Diseases / Q000378:metabolism; D048429:Cell Size; D005786:Gene Expression Regulation; D006801:Humans; D017136:Ion Transport; D009131:Muscle, Smooth, Vascular / Q000378:metabolism* / Q000473:pathology; D010982:Platelet-Derived Growth Factor / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology*; D027981:Symporters / Q000235:genetics / Q000378:metabolism*; D014664:Vasodilation / Q000502:physiology*; D000096922:K Cl- Cotransporters
D010982:Platelet-Derived Growth Factor; D027981:Symporters; D000096922:K Cl- Cotransporters