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Modulation of smooth muscle contraction by cyclic nucleotides in mice lacking cGMP-dependent-kinase I.

Bonnevier, Johan LU ; Fassler, Reinhard; Somlyo, Andrew P.; Somlyo, Avril V. and Arner, Anders LU (2004) In Journal of Biological Chemistry 279(7). p.5146-5151
Abstract
The cGMP-dependent protein kinase (PKG) is the main mediator of nitric oxide-induced relaxation of smooth muscle. Although this pathway is well established, the cellular action of PKG, nitric oxide, and cGMP is complex and not fully understood. A cross-talk between the cGMP-PKG and other pathways (e.g. cAMP-protein kinase A) seems to exist. We have explored cGMP- and cAMP-dependent relaxation of smooth muscle using PKG-deficient mice (cGKI–/–). In intact ileum strips of wild type mice (cGKI+/+), 8-Br-cGMP inhibited the sustained phase of carbachol contractions by ~80%. The initial peak was less inhibited (~30%). This relaxation was associated with a reduction in intracellular [Ca2+] and decreased Ca2+ sensitivity. Contractions of cGKI–/–... (More)
The cGMP-dependent protein kinase (PKG) is the main mediator of nitric oxide-induced relaxation of smooth muscle. Although this pathway is well established, the cellular action of PKG, nitric oxide, and cGMP is complex and not fully understood. A cross-talk between the cGMP-PKG and other pathways (e.g. cAMP-protein kinase A) seems to exist. We have explored cGMP- and cAMP-dependent relaxation of smooth muscle using PKG-deficient mice (cGKI–/–). In intact ileum strips of wild type mice (cGKI+/+), 8-Br-cGMP inhibited the sustained phase of carbachol contractions by ~80%. The initial peak was less inhibited (~30%). This relaxation was associated with a reduction in intracellular [Ca2+] and decreased Ca2+ sensitivity. Contractions of cGKI–/– ileum were not influenced by 8-Br-cGMP. EC50 for 8-Br-cGMP for PKG was estimated to be 10 nM. PKG-independent relaxation by 8-Br-cGMP had an EC50 of 10 µM. Relaxation by cAMP (~50% at 100 µM), Ca2+ sensitivity of force, and force potentiation by GTP{gamma}S were similar in cGKI+/+ and cGKI–/– tissues. The results show that PKG is the main target for cGMP-induced relaxation in intestinal smooth muscle. cGMP desensitize the contractile system to Ca2+ via PKG. PKG-independent pathways are activated at 1000-fold higher cGMP concentrations. Relaxation by cAMP can occur independently of PKG. Long term deficiency of PKG does not lead to an apparent up-regulation of the cAMP-dependent pathways or changes in Ca2+ sensitivity. (Less)
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author
publishing date
type
Contribution to journal
publication status
published
subject
in
Journal of Biological Chemistry
volume
279
issue
7
pages
5146 - 5151
publisher
ASBMB
external identifiers
  • wos:000188776500014
  • pmid:14610087
  • scopus:1242294512
ISSN
1083-351X
DOI
10.1074/jbc.M306532200
language
English
LU publication?
no
id
abeb8c95-6735-4e42-9c3d-6beaca8bb5ac (old id 119040)
date added to LUP
2007-07-10 14:44:07
date last changed
2017-01-01 05:11:21
@article{abeb8c95-6735-4e42-9c3d-6beaca8bb5ac,
  abstract     = {The cGMP-dependent protein kinase (PKG) is the main mediator of nitric oxide-induced relaxation of smooth muscle. Although this pathway is well established, the cellular action of PKG, nitric oxide, and cGMP is complex and not fully understood. A cross-talk between the cGMP-PKG and other pathways (e.g. cAMP-protein kinase A) seems to exist. We have explored cGMP- and cAMP-dependent relaxation of smooth muscle using PKG-deficient mice (cGKI–/–). In intact ileum strips of wild type mice (cGKI+/+), 8-Br-cGMP inhibited the sustained phase of carbachol contractions by ~80%. The initial peak was less inhibited (~30%). This relaxation was associated with a reduction in intracellular [Ca2+] and decreased Ca2+ sensitivity. Contractions of cGKI–/– ileum were not influenced by 8-Br-cGMP. EC50 for 8-Br-cGMP for PKG was estimated to be 10 nM. PKG-independent relaxation by 8-Br-cGMP had an EC50 of 10 µM. Relaxation by cAMP (~50% at 100 µM), Ca2+ sensitivity of force, and force potentiation by GTP{gamma}S were similar in cGKI+/+ and cGKI–/– tissues. The results show that PKG is the main target for cGMP-induced relaxation in intestinal smooth muscle. cGMP desensitize the contractile system to Ca2+ via PKG. PKG-independent pathways are activated at 1000-fold higher cGMP concentrations. Relaxation by cAMP can occur independently of PKG. Long term deficiency of PKG does not lead to an apparent up-regulation of the cAMP-dependent pathways or changes in Ca2+ sensitivity.},
  author       = {Bonnevier, Johan and Fassler, Reinhard and Somlyo, Andrew P. and Somlyo, Avril V. and Arner, Anders},
  issn         = {1083-351X},
  language     = {eng},
  number       = {7},
  pages        = {5146--5151},
  publisher    = {ASBMB},
  series       = {Journal of Biological Chemistry},
  title        = {Modulation of smooth muscle contraction by cyclic nucleotides in mice lacking cGMP-dependent-kinase I.},
  url          = {http://dx.doi.org/10.1074/jbc.M306532200},
  volume       = {279},
  year         = {2004},
}