Modulation of smooth muscle contraction by cyclic nucleotides in mice lacking cGMP-dependent-kinase I.
(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)
Please use this url to cite or link to this publication:
https://lup.lub.lu.se/record/119040
- author
- Bonnevier, Johan LU ; Fassler, Reinhard ; Somlyo, Andrew P. ; Somlyo, Avril V. and Arner, Anders LU
- publishing date
- 2004
- type
- Contribution to journal
- publication status
- published
- subject
- in
- Journal of Biological Chemistry
- volume
- 279
- issue
- 7
- pages
- 5146 - 5151
- publisher
- American Society for Biochemistry and Molecular Biology
- 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
- 2016-04-01 12:29:26
- date last changed
- 2022-03-21 05:05:41
@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 = {{American Society for Biochemistry and Molecular Biology}},
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}},
doi = {{10.1074/jbc.M306532200}},
volume = {{279}},
year = {{2004}},
}