Skip to main content
PMC home page
The EMBO Journal logoLink to The EMBO Journal
. 1998 Jun 1;17(11):3045–3051. doi: 10.1093/emboj/17.11.3045

Defective smooth muscle regulation in cGMP kinase I-deficient mice.

A Pfeifer 1, P Klatt 1, S Massberg 1, L Ny 1, M Sausbier 1, C Hirneiss 1, G X Wang 1, M Korth 1, A Aszódi 1, K E Andersson 1, F Krombach 1, A Mayerhofer 1, P Ruth 1, R Fässler 1, F Hofmann 1
PMCID: PMC1170644  PMID: 9606187

Abstract

Regulation of smooth muscle contractility is essential for many important biological processes such as tissue perfusion, cardiovascular haemostasis and gastrointestinal motility. While an increase in calcium initiates smooth muscle contraction, relaxation can be induced by cGMP or cAMP. cGMP-dependent protein kinase I (cGKI) has been suggested as a major mediator of the relaxant effects of both nucleotides. To study the biological role of cGKI and its postulated cross-activation by cAMP, we inactivated the gene coding for cGKI in mice. Loss of cGKI abolishes nitric oxide (NO)/cGMP-dependent relaxation of smooth muscle, resulting in severe vascular and intestinal dysfunctions. However, cGKI-deficient smooth muscle responded normally to cAMP, indicating that cAMP and cGMP signal via independent pathways, with cGKI being the specific mediator of the NO/cGMP effects in murine smooth muscle.

Full Text

The Full Text of this article is available as a PDF (363.3 KB).

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Burns A. J., Lomax A. E., Torihashi S., Sanders K. M., Ward S. M. Interstitial cells of Cajal mediate inhibitory neurotransmission in the stomach. Proc Natl Acad Sci U S A. 1996 Oct 15;93(21):12008–12013. doi: 10.1073/pnas.93.21.12008. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Chao A. C., de Sauvage F. J., Dong Y. J., Wagner J. A., Goeddel D. V., Gardner P. Activation of intestinal CFTR Cl- channel by heat-stable enterotoxin and guanylin via cAMP-dependent protein kinase. EMBO J. 1994 Mar 1;13(5):1065–1072. doi: 10.1002/j.1460-2075.1994.tb06355.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Cornwell T. L., Lincoln T. M. Regulation of intracellular Ca2+ levels in cultured vascular smooth muscle cells. Reduction of Ca2+ by atriopeptin and 8-bromo-cyclic GMP is mediated by cyclic GMP-dependent protein kinase. J Biol Chem. 1989 Jan 15;264(2):1146–1155. [PubMed] [Google Scholar]
  4. Desai K. M., Zembowicz A., Sessa W. C., Vane J. R. Nitroxergic nerves mediate vagally induced relaxation in the isolated stomach of the guinea pig. Proc Natl Acad Sci U S A. 1991 Dec 15;88(24):11490–11494. doi: 10.1073/pnas.88.24.11490. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Felbel J., Trockur B., Ecker T., Landgraf W., Hofmann F. Regulation of cytosolic calcium by cAMP and cGMP in freshly isolated smooth muscle cells from bovine trachea. J Biol Chem. 1988 Nov 15;263(32):16764–16771. [PubMed] [Google Scholar]
  6. Fleming I., Busse R. Control and consequences of endothelial nitric oxide formation. Adv Pharmacol. 1995;34:187–206. doi: 10.1016/s1054-3589(08)61086-8. [DOI] [PubMed] [Google Scholar]
  7. Francis S. H., Corbin J. D. Progress in understanding the mechanism and function of cyclic GMP-dependent protein kinase. Adv Pharmacol. 1994;26:115–170. doi: 10.1016/s1054-3589(08)60053-8. [DOI] [PubMed] [Google Scholar]
  8. Furchgott R. F., Zawadzki J. V. The obligatory role of endothelial cells in the relaxation of arterial smooth muscle by acetylcholine. Nature. 1980 Nov 27;288(5789):373–376. doi: 10.1038/288373a0. [DOI] [PubMed] [Google Scholar]
  9. Fässler R., Meyer M. Consequences of lack of beta 1 integrin gene expression in mice. Genes Dev. 1995 Aug 1;9(15):1896–1908. doi: 10.1101/gad.9.15.1896. [DOI] [PubMed] [Google Scholar]
  10. Geiger J., Nolte C., Butt E., Sage S. O., Walter U. Role of cGMP and cGMP-dependent protein kinase in nitrovasodilator inhibition of agonist-evoked calcium elevation in human platelets. Proc Natl Acad Sci U S A. 1992 Feb 1;89(3):1031–1035. doi: 10.1073/pnas.89.3.1031. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Hanks S. K., Quinn A. M., Hunter T. The protein kinase family: conserved features and deduced phylogeny of the catalytic domains. Science. 1988 Jul 1;241(4861):42–52. doi: 10.1126/science.3291115. [DOI] [PubMed] [Google Scholar]
  12. Hofmann F., Dostmann W., Keilbach A., Landgraf W., Ruth P. Structure and physiological role of cGMP-dependent protein kinase. Biochim Biophys Acta. 1992 Apr 30;1135(1):51–60. doi: 10.1016/0167-4889(92)90165-8. [DOI] [PubMed] [Google Scholar]
  13. Huang P. L., Huang Z., Mashimo H., Bloch K. D., Moskowitz M. A., Bevan J. A., Fishman M. C. Hypertension in mice lacking the gene for endothelial nitric oxide synthase. Nature. 1995 Sep 21;377(6546):239–242. doi: 10.1038/377239a0. [DOI] [PubMed] [Google Scholar]
  14. Ignarro L. J., Buga G. M., Wood K. S., Byrns R. E., Chaudhuri G. Endothelium-derived relaxing factor produced and released from artery and vein is nitric oxide. Proc Natl Acad Sci U S A. 1987 Dec;84(24):9265–9269. doi: 10.1073/pnas.84.24.9265. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Jarchau T., Häusler C., Markert T., Pöhler D., Vanderkerckhove J., De Jonge H. R., Lohmann S. M., Walter U. Cloning, expression, and in situ localization of rat intestinal cGMP-dependent protein kinase II. Proc Natl Acad Sci U S A. 1994 Sep 27;91(20):9426–9430. doi: 10.1073/pnas.91.20.9426. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Jiang H., Colbran J. L., Francis S. H., Corbin J. D. Direct evidence for cross-activation of cGMP-dependent protein kinase by cAMP in pig coronary arteries. J Biol Chem. 1992 Jan 15;267(2):1015–1019. [PubMed] [Google Scholar]
  17. Jin J. G., Murthy K. S., Grider J. R., Makhlouf G. M. Stoichiometry of neurally induced VIP release, NO formation, and relaxation in rabbit and rat gastric muscle. Am J Physiol. 1996 Aug;271(2 Pt 1):G357–G369. doi: 10.1152/ajpgi.1996.271.2.G357. [DOI] [PubMed] [Google Scholar]
  18. Keilbach A., Ruth P., Hofmann F. Detection of cGMP dependent protein kinase isozymes by specific antibodies. Eur J Biochem. 1992 Sep 1;208(2):467–473. doi: 10.1111/j.1432-1033.1992.tb17209.x. [DOI] [PubMed] [Google Scholar]
  19. Kleppisch T., Nelson M. T. Adenosine activates ATP-sensitive potassium channels in arterial myocytes via A2 receptors and cAMP-dependent protein kinase. Proc Natl Acad Sci U S A. 1995 Dec 19;92(26):12441–12445. doi: 10.1073/pnas.92.26.12441. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Landgraf W., Hullin R., Göbel C., Hofmann F. Phosphorylation of cGMP-dependent protein kinase increases the affinity for cyclic AMP. Eur J Biochem. 1986 Jan 2;154(1):113–117. doi: 10.1111/j.1432-1033.1986.tb09365.x. [DOI] [PubMed] [Google Scholar]
  21. Lincoln T. M., Cornwell T. L., Taylor A. E. cGMP-dependent protein kinase mediates the reduction of Ca2+ by cAMP in vascular smooth muscle cells. Am J Physiol. 1990 Mar;258(3 Pt 1):C399–C407. doi: 10.1152/ajpcell.1990.258.3.C399. [DOI] [PubMed] [Google Scholar]
  22. Lincoln T. M., Komalavilas P., Boerth N. J., MacMillan-Crow L. A., Cornwell T. L. cGMP signaling through cAMP- and cGMP-dependent protein kinases. Adv Pharmacol. 1995;34:305–322. doi: 10.1016/s1054-3589(08)61094-7. [DOI] [PubMed] [Google Scholar]
  23. Lohmann S. M., Vaandrager A. B., Smolenski A., Walter U., De Jonge H. R. Distinct and specific functions of cGMP-dependent protein kinases. Trends Biochem Sci. 1997 Aug;22(8):307–312. doi: 10.1016/s0968-0004(97)01086-4. [DOI] [PubMed] [Google Scholar]
  24. Murad F. Regulation of cytosolic guanylyl cyclase by nitric oxide: the NO-cyclic GMP signal transduction system. Adv Pharmacol. 1994;26:19–33. doi: 10.1016/s1054-3589(08)60049-6. [DOI] [PubMed] [Google Scholar]
  25. Ny L., Larsson B., Alm P., Ekström P., Fahrenkrug J., Hannibal J., Andersson K. E. Distribution and effects of pituitary adenylate cyclase activating peptide in cat and human lower oesophageal sphincter. Br J Pharmacol. 1995 Dec;116(7):2873–2880. doi: 10.1111/j.1476-5381.1995.tb15939.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. Orstavik S., Natarajan V., Taskén K., Jahnsen T., Sandberg M. Characterization of the human gene encoding the type I alpha and type I beta cGMP-dependent protein kinase (PRKG1). Genomics. 1997 Jun 1;42(2):311–318. doi: 10.1006/geno.1997.4743. [DOI] [PubMed] [Google Scholar]
  27. Palmer R. M., Ferrige A. G., Moncada S. Nitric oxide release accounts for the biological activity of endothelium-derived relaxing factor. Nature. 1987 Jun 11;327(6122):524–526. doi: 10.1038/327524a0. [DOI] [PubMed] [Google Scholar]
  28. Pfeifer A., Aszódi A., Seidler U., Ruth P., Hofmann F., Fässler R. Intestinal secretory defects and dwarfism in mice lacking cGMP-dependent protein kinase II. Science. 1996 Dec 20;274(5295):2082–2086. doi: 10.1126/science.274.5295.2082. [DOI] [PubMed] [Google Scholar]
  29. Rapoport R. M., Draznin M. B., Murad F. Endothelium-dependent relaxation in rat aorta may be mediated through cyclic GMP-dependent protein phosphorylation. Nature. 1983 Nov 10;306(5939):174–176. doi: 10.1038/306174a0. [DOI] [PubMed] [Google Scholar]
  30. Rasmussen H., Kelley G., Douglas J. S. Interactions between Ca2+ and cAMP messenger system in regulation of airway smooth muscle contraction. Am J Physiol. 1990 Jun;258(6 Pt 1):L279–L288. doi: 10.1152/ajplung.1990.258.6.L279. [DOI] [PubMed] [Google Scholar]
  31. Ruth P., Wang G. X., Boekhoff I., May B., Pfeifer A., Penner R., Korth M., Breer H., Hofmann F. Transfected cGMP-dependent protein kinase suppresses calcium transients by inhibition of inositol 1,4,5-trisphosphate production. Proc Natl Acad Sci U S A. 1993 Apr 1;90(7):2623–2627. doi: 10.1073/pnas.90.7.2623. [DOI] [PMC free article] [PubMed] [Google Scholar]
  32. Sandberg M., Natarajan V., Ronander I., Kalderon D., Walter U., Lohmann S. M., Jahnsen T. Molecular cloning and predicted full-length amino acid sequence of the type I beta isozyme of cGMP-dependent protein kinase from human placenta. Tissue distribution and developmental changes in rat. FEBS Lett. 1989 Sep 25;255(2):321–329. doi: 10.1016/0014-5793(89)81114-7. [DOI] [PubMed] [Google Scholar]
  33. Sanders K. M., Ward S. M. Nitric oxide as a mediator of nonadrenergic noncholinergic neurotransmission. Am J Physiol. 1992 Mar;262(3 Pt 1):G379–G392. doi: 10.1152/ajpgi.1992.262.3.G379. [DOI] [PubMed] [Google Scholar]
  34. Shesely E. G., Maeda N., Kim H. S., Desai K. M., Krege J. H., Laubach V. E., Sherman P. A., Sessa W. C., Smithies O. Elevated blood pressures in mice lacking endothelial nitric oxide synthase. Proc Natl Acad Sci U S A. 1996 Nov 12;93(23):13176–13181. doi: 10.1073/pnas.93.23.13176. [DOI] [PMC free article] [PubMed] [Google Scholar]
  35. Smith J. A., Francis S. H., Walsh K. A., Kumar S., Corbin J. D. Autophosphorylation of type Ibeta cGMP-dependent protein kinase increases basal catalytic activity and enhances allosteric activation by cGMP or cAMP. J Biol Chem. 1996 Aug 23;271(34):20756–20762. doi: 10.1074/jbc.271.34.20756. [DOI] [PubMed] [Google Scholar]
  36. Somlyo A. P. Signal transduction. Rhomantic interludes raise blood pressure. Nature. 1997 Oct 30;389(6654):908-9, 911. doi: 10.1038/40002. [DOI] [PubMed] [Google Scholar]
  37. Somlyo A. P., Somlyo A. V. Signal transduction and regulation in smooth muscle. Nature. 1994 Nov 17;372(6503):231–236. doi: 10.1038/372231a0. [DOI] [PubMed] [Google Scholar]
  38. Uhler M. D. Cloning and expression of a novel cyclic GMP-dependent protein kinase from mouse brain. J Biol Chem. 1993 Jun 25;268(18):13586–13591. [PubMed] [Google Scholar]
  39. Waldmann R., Bauer S., Göbel C., Hofmann F., Jakobs K. H., Walter U. Demonstration of cGMP-dependent protein kinase and cGMP-dependent phosphorylation in cell-free extracts of platelets. Eur J Biochem. 1986 Jul 1;158(1):203–210. doi: 10.1111/j.1432-1033.1986.tb09739.x. [DOI] [PubMed] [Google Scholar]
  40. Wernet W., Flockerzi V., Hofmann F. The cDNA of the two isoforms of bovine cGMP-dependent protein kinase. FEBS Lett. 1989 Jul 17;251(1-2):191–196. doi: 10.1016/0014-5793(89)81453-x. [DOI] [PubMed] [Google Scholar]

Articles from The EMBO Journal are provided here courtesy of Nature Publishing Group

RESOURCES