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Increased PDE5 activity and decreased Rho kinase and PKC activities in colonic muscle from caveolin-1-/- mice impair the peristaltic reflex and propulsion.
Increased PDE5 activity and decreased Rho kinase and PKC activities in colonic muscle from caveolin-1-/- mice impair the peristaltic reflex and propulsion.
- Source :
-
American journal of physiology. Gastrointestinal and liver physiology [Am J Physiol Gastrointest Liver Physiol] 2013 Dec; Vol. 305 (12), pp. G964-74. Date of Electronic Publication: 2013 Oct 24. - Publication Year :
- 2013
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Abstract
- Caveolae are specialized regions of the plasma membrane that concentrate receptors and associated signaling molecules critical in regulation of cellular response to transmitters and hormones. We have determined the effects of caveolin-1 (Cav-1) deletion, caveolin-1 siRNA, and caveolar disruption in mice on the signaling pathways that mediate contraction and relaxation in colonic smooth muscle and on the components of the peristaltic reflex in isolated tissue and propulsion in intact colonic segments. In Cav-1-/- mice, both relaxation and contraction were decreased in smooth muscle cells and muscle strips, as well as during both phases of the peristaltic reflex and colonic propulsion. The decrease in relaxation in response to the nitric oxide (NO) donor was accompanied by a decrease in cGMP levels and an increase in phosphodiesterase 5 (PDE5) activity. Relaxation by a PDE5-resistant cGMP analog was not affected in smooth muscle of Cav-1-/- mice, suggesting that inhibition of relaxation was due to augmentation of PDE5 activity. Similar effects on relaxation, PDE5 and cGMP were obtained in muscle cells upon disruption of caveolae by methyl-β-cyclodextrin or suppression of Cav-1. Sustained contraction mediated via inhibition of myosin light chain phosphatase (MLCP) activity is regulated by Rho kinase and PKC via phosphorylation of two endogenous inhibitors of MLCP: myosin phosphatase-targeting subunit (MYPT1) and 17-kDa PKC-potentiated protein phosphatase 1 inhibitor protein (CPI-17), respectively. The activity of both enzymes and phosphorylation of MYPT1 and CPI-17 were decreased in smooth muscle from Cav-1-/- mice. We conclude that the integrity of caveolae is essential for contractile and relaxant activity in colonic smooth muscle and the maintenance of neuromuscular function at organ level.
- Subjects :
- Animals
Gastrointestinal Transit drug effects
Gastrointestinal Transit physiology
Mice
Mice, Inbred C57BL
Models, Animal
Muscle, Smooth metabolism
Muscle, Smooth physiology
Myosin-Light-Chain Phosphatase metabolism
Signal Transduction physiology
beta-Cyclodextrins metabolism
Caveolin 1 pharmacology
Colon metabolism
Colon physiology
Cyclic Nucleotide Phosphodiesterases, Type 5 metabolism
Peristalsis drug effects
Peristalsis physiology
Protein Kinase C metabolism
rho-Associated Kinases metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1522-1547
- Volume :
- 305
- Issue :
- 12
- Database :
- MEDLINE
- Journal :
- American journal of physiology. Gastrointestinal and liver physiology
- Publication Type :
- Academic Journal
- Accession number :
- 24157969
- Full Text :
- https://doi.org/10.1152/ajpgi.00165.2013