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. 1996 Feb;117(3):419–426. doi: 10.1111/j.1476-5381.1996.tb15207.x

Modulation of agonist-induced phosphoinositide metabolism, Ca2+ signalling and contraction of airway smooth muscle by cyclic AMP-dependent mechanisms.

B H Hoiting 1, H Meurs 1, M Schuiling 1, R Kuipers 1, C R Elzinga 1, J Zaagsma 1
PMCID: PMC1909321  PMID: 8821529

Abstract

1. The effects of increased cellular cyclic AMP levels induced by isoprenaline, forskolin and 8-bromoadenosine 3':5'-cyclic monophosphate (8-Br-cyclic AMP) on phosphoinositide metabolism and changes in intracellular Ca2+ elicited by methacholine and histamine were examined in bovine isolated tracheal smooth muscle (BTSM) cells. 2. Isoprenaline (pD2 (-log10 EC50) = 6.32 +/- 0.24) and forskolin (pD2 = 5.6 +/- 0.05) enhanced cyclic AMP levels in a concentration-dependent fashion in these cells, while methacholine (pD2 = 5.64 +/- 0.12) and histamine (pD2 = 4.90 +/- 0.04) caused a concentration-related increase in [3H]-inositol phosphates (IP) accumulation in the presence of 10 mM LiCl. 3. Preincubation of the cells (5 min, 37 degrees C) with isoprenaline (1 microM), forskolin (10 microM) and 8-Br-cyclic AMP (1 mM) did not affect the IP accumulation induced by methacholine, but significantly reduced the maximal IP production by histamine (1 mM). However, the effect of isoprenaline was small (15.0 +/- 0.6% inhibition) and insignificant at histamine concentrations between 0.1 and 100 microM. 4. Both methacholine and histamine induced a fast (max. in 0.5-2 s) and transient increase of intracellular Ca2+ concentration ([Ca2+]i) followed by a sustained phase lasting several minutes. EGTA (5 mM) attenuated the sustained phase, indicating that this phase depends on extracellular Ca2+. 5. Preincubation of the cells (5 min, 37 degrees C) with isoprenaline (1 microM), forskolin (10 microM) and 8-Br-cyclic AMP (1 microM) significantly attenuated both the Ca(2+)-transient and the sustained phase generated at equipotent IP producing concentrations of 1 microM methacholine and 100 microM histamine (approx. 40% of maximal methacholine-induced IP response), but did not affect changes in [Ca2+]i induced by 100 microM methacholine (95.2 +/- 3.5% of maximal methacholine-induced IP response). 6. Significant correlations were found between the isoprenaline-induced inhibition of BTSM contraction and inhibition of Ca2+ mobilization or influx induced by methacholine and histamine, that were similar for each contractile agonist. 7. These data indicate that (a) cyclic AMP-dependent inhibition of Ca2+ mobilization in BTSM cells is not primarily caused by attenuation of IP production, suggesting that cyclic AMP induced protein kinase A (PKA) activation is effective at a different level in the [Ca2+]i homeostasis, (b) that attenuation of intracellular Ca2+ concentration plays a major role in beta-adrenoceptor-mediated relaxation of methacholine- and histamine-induced airway smooth muscle contraction, and (c) that the relative resistance of the muscarinic agonist-induced contraction to beta-adrenoceptor agonists, especially at (supra) maximal contractile concentrations is largely determined by its higher potency in inducing intracellular Ca2+ changes.

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Selected References

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  1. Abdel-Latif A. A. Biochemical and functional interactions between the inositol 1,4,5-trisphosphate-Ca2+ and cyclic AMP signalling systems in smooth muscle. Cell Signal. 1991;3(5):371–385. doi: 10.1016/0898-6568(91)90068-6. [DOI] [PubMed] [Google Scholar]
  2. Baron C. B., Cunningham M., Strauss J. F., 3rd, Coburn R. F. Pharmacomechanical coupling in smooth muscle may involve phosphatidylinositol metabolism. Proc Natl Acad Sci U S A. 1984 Nov;81(21):6899–6903. doi: 10.1073/pnas.81.21.6899. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Brown B. L., Albano J. D., Ekins R. P., Sgherzi A. M. A simple and sensitive saturation assay method for the measurement of adenosine 3':5'-cyclic monophosphate. Biochem J. 1971 Feb;121(3):561–562. doi: 10.1042/bj1210561. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Daykin K., Widdop S., Hall I. P. Control of histamine induced inositol phospholipid hydrolysis in cultured human tracheal smooth muscle cells. Eur J Pharmacol. 1993 Jul 15;246(2):135–140. doi: 10.1016/0922-4106(93)90090-v. [DOI] [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. Grynkiewicz G., Poenie M., Tsien R. Y. A new generation of Ca2+ indicators with greatly improved fluorescence properties. J Biol Chem. 1985 Mar 25;260(6):3440–3450. [PubMed] [Google Scholar]
  7. Hall I. P., Donaldson J., Hill S. J. Inhibition of histamine-stimulated inositol phospholipid hydrolysis by agents which increase cyclic AMP levels in bovine tracheal smooth muscle. Br J Pharmacol. 1989 Jun;97(2):603–613. doi: 10.1111/j.1476-5381.1989.tb11992.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Hall I. P., Hill S. J. Beta-adrenoceptor stimulation inhibits histamine-stimulated inositol phospholipid hydrolysis in bovine tracheal smooth muscle. Br J Pharmacol. 1988 Dec;95(4):1204–1212. doi: 10.1111/j.1476-5381.1988.tb11757.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Hashimoto T., Hirata M., Ito Y. A role for inositol 1,4,5-trisphosphate in the initiation of agonist-induced contractions of dog tracheal smooth muscle. Br J Pharmacol. 1985 Sep;86(1):191–199. doi: 10.1111/j.1476-5381.1985.tb09449.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Jenne J. W., Shaughnessy T. K., Druz W. S., Manfredi C. J., Vestal R. E. In vivo functional antagonism between isoproterenol and bronchoconstrictants in the dog. J Appl Physiol (1985) 1987 Aug;63(2):812–819. doi: 10.1152/jappl.1987.63.2.812. [DOI] [PubMed] [Google Scholar]
  11. Jones C. A., Madison J. M., Tom-Moy M., Brown J. K. Muscarinic cholinergic inhibition of adenylate cyclase in airway smooth muscle. Am J Physiol. 1987 Jul;253(1 Pt 1):C97–104. doi: 10.1152/ajpcell.1987.253.1.C97. [DOI] [PubMed] [Google Scholar]
  12. Kajita J., Yamaguchi H. Calcium mobilization by muscarinic cholinergic stimulation in bovine single airway smooth muscle. Am J Physiol. 1993 May;264(5 Pt 1):L496–L503. doi: 10.1152/ajplung.1993.264.5.L496. [DOI] [PubMed] [Google Scholar]
  13. Madison J. M., Brown J. K. Differential inhibitory effects of forskolin, isoproterenol, and dibutyryl cyclic adenosine monophosphate on phosphoinositide hydrolysis in canine tracheal smooth muscle. J Clin Invest. 1988 Oct;82(4):1462–1465. doi: 10.1172/JCI113752. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Meurs H., Roffel A. F., Postema J. B., Timmermans A., Elzinga C. R., Kauffman H. F., Zaagsma J. Evidence for a direct relationship between phosphoinositide metabolism and airway smooth muscle contraction induced by muscarinic agonists. Eur J Pharmacol. 1988 Nov 1;156(2):271–274. doi: 10.1016/0014-2999(88)90331-7. [DOI] [PubMed] [Google Scholar]
  15. Meurs H., Timmermans A., Van Amsterdam R. G., Brouwer F., Kauffman H. F., Zaagsma J. Muscarinic receptors in human airway smooth muscle are coupled to phosphoinositide metabolism. Eur J Pharmacol. 1989 May 19;164(2):369–371. doi: 10.1016/0014-2999(89)90480-9. [DOI] [PubMed] [Google Scholar]
  16. Murray R. K., Kotlikoff M. I. Receptor-activated calcium influx in human airway smooth muscle cells. J Physiol. 1991 Apr;435:123–144. doi: 10.1113/jphysiol.1991.sp018501. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Offer G. J., Chilvers E. R., Nahorski S. R. Beta-adrenoceptor induced inhibition of muscarinic receptor-stimulated phosphoinositide metabolism is agonist specific in bovine tracheal smooth muscle. Eur J Pharmacol. 1991 Jul 12;207(3):243–248. doi: 10.1016/0922-4106(91)90036-h. [DOI] [PubMed] [Google Scholar]
  18. Ozaki H., Kwon S. C., Tajimi M., Karaki H. Changes in cytosolic CA2+ and contraction induced by various stimulants and relaxants in canine tracheal smooth muscle. Pflugers Arch. 1990 Jun;416(4):351–359. doi: 10.1007/BF00370740. [DOI] [PubMed] [Google Scholar]
  19. Roffel A. F., Meurs H., Elzinga C. R., Zaagsma J. Characterization of the muscarinic receptor subtype involved in phosphoinositide metabolism in bovine tracheal smooth muscle. Br J Pharmacol. 1990 Feb;99(2):293–296. doi: 10.1111/j.1476-5381.1990.tb14697.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Russell J. A. Differential inhibitory effect of isoproterenol on contractions of canine airways. J Appl Physiol Respir Environ Exerc Physiol. 1984 Sep;57(3):801–807. doi: 10.1152/jappl.1984.57.3.801. [DOI] [PubMed] [Google Scholar]
  21. Sim S. S., Kim J. W., Rhee S. G. Regulation of D-myo-inositol 1,4,5-trisphosphate 3-kinase by cAMP-dependent protein kinase and protein kinase C. J Biol Chem. 1990 Jun 25;265(18):10367–10372. [PubMed] [Google Scholar]
  22. Suematsu E., Hirata M., Kuriyama H. Effects of cAMP- and cGMP-dependent protein kinases, and calmodulin on Ca2+ uptake by highly purified sarcolemmal vesicles of vascular smooth muscle. Biochim Biophys Acta. 1984 Jun 13;773(1):83–90. doi: 10.1016/0005-2736(84)90552-2. [DOI] [PubMed] [Google Scholar]
  23. Takuwa Y., Takuwa N., Rasmussen H. The effects of isoproterenol on intracellular calcium concentration. J Biol Chem. 1988 Jan 15;263(2):762–768. [PubMed] [Google Scholar]
  24. Taylor D. A., Bowman B. F., Stull J. T. Cytoplasmic Ca2+ is a primary determinant for myosin phosphorylation in smooth muscle cells. J Biol Chem. 1989 Apr 15;264(11):6207–6213. [PubMed] [Google Scholar]
  25. Twort C. H., van Breemen C. Human airway smooth muscle in cell culture: control of the intracellular calcium store. Pulm Pharmacol. 1989;2(1):45–53. doi: 10.1016/s0952-0600(89)80009-2. [DOI] [PubMed] [Google Scholar]
  26. Van Amsterdam R. G., Meurs H., Brouwer F., Postema J. B., Timmermans A., Zaagsma J. Role of phosphoinositide metabolism in functional antagonism of airway smooth muscle contraction by beta-adrenoceptor agonists. Eur J Pharmacol. 1989 May 11;172(2):175–183. doi: 10.1016/0922-4106(89)90008-4. [DOI] [PubMed] [Google Scholar]
  27. Van Amsterdam R. G., Meurs H., Ten Berge R. E., Veninga N. C., Brouwer F., Zaagsma J. Role of phosphoinositide metabolism in human bronchial smooth muscle contraction and in functional antagonism by beta-adrenoceptor agonists. Am Rev Respir Dis. 1990 Nov;142(5):1124–1128. doi: 10.1164/ajrccm/142.5.1124. [DOI] [PubMed] [Google Scholar]
  28. Velema J., Noordam P. C., Zaagsma J. Comparison of cyclic AMP-dependent phosphorylation of sarcolemma and sarcoplasmic reticulum from rat cardiac ventricle muscle. Int J Biochem. 1983;15(5):675–684. doi: 10.1016/0020-711x(83)90192-1. [DOI] [PubMed] [Google Scholar]
  29. Volpe P., Alderson-Lang B. H. Regulation of inositol 1,4,5-trisphosphate-induced Ca2+ release. II. Effect of cAMP-dependent protein kinase. Am J Physiol. 1990 Jun;258(6 Pt 1):C1086–C1091. doi: 10.1152/ajpcell.1990.258.6.C1086. [DOI] [PubMed] [Google Scholar]
  30. Yamaguchi H., Kajita J., Madison J. M. Isoproterenol increases peripheral [Ca2+]i and decreases inner [Ca2+]i in single airway smooth muscle cells. Am J Physiol. 1995 Mar;268(3 Pt 1):C771–C779. doi: 10.1152/ajpcell.1995.268.3.C771. [DOI] [PubMed] [Google Scholar]
  31. Yang C. M., Chou S. P., Sung T. C. Muscarinic receptor subtypes coupled to generation of different second messengers in isolated tracheal smooth muscle cells. Br J Pharmacol. 1991 Nov;104(3):613–618. doi: 10.1111/j.1476-5381.1991.tb12478.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  32. Zhou H. L., Newsholme S. J., Torphy T. J. Agonist-related differences in the relationship between cAMP content and protein kinase activity in canine trachealis. J Pharmacol Exp Ther. 1992 Jun;261(3):1260–1267. [PubMed] [Google Scholar]

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