Skip to main content
NCBI home page
British Journal of Pharmacology logoLink to British Journal of Pharmacology
. 1991 Nov;104(3):613–618. doi: 10.1111/j.1476-5381.1991.tb12478.x

Muscarinic receptor subtypes coupled to generation of different second messengers in isolated tracheal smooth muscle cells.

C M Yang 1, S P Chou 1, T C Sung 1
PMCID: PMC1908245  PMID: 1665744

Abstract

1. Activation of muscarinic receptor subtypes leads to contraction, an increase in the accumulation of inositol phosphates (IPs) and a decrease in adenosine 3': 5'-cyclic monophosphate (cyclic AMP) synthesis in tracheal smooth muscle. The concentrations of carbachol that produced a half-maximal effect (EC50) in inhibition of cyclic AMP generation, stimulation of IPs formation and contraction were 15 nM, 2.0 microM and 0.17 microM, respectively. 2. Pirenzepine, a selective M1 antagonist, displayed a low affinity for antagonizing cyclic AMP inhibition, IPs formation and contraction induced by carbachol (pKB = 6.8, 7.0, and 7.1, respectively). 3. Methoctramine, a cardioselective M2 antagonist, blocked cyclic AMP inhibition with a high affinity (pKB = 7.5), while it antagonized IPs formation and contraction with a low affinity (pKB = 6.2 and 6.1, respectively). 4. 4-Diphenylacetoxy-N-methylpiperidine (4-DAMP), a selective smooth muscle M3 antagonist, possessed a high affinity in blocking IPs formation (pKB = 8.8) and contraction (pKB = 9.2) as well as a low affinity for antagonism of cyclic AMP inhibition (pKB = 8.1). 5. In conclusion, we have demonstrated that M2 and M3 receptor subtypes are coupled to different effector systems in tracheal smooth muscle. An M1 receptor subtype is not involved in the generation of the second messengers examined. Inhibition of cyclic AMP formation may be coupled to the M2 receptor subtype. The accumulation of IPs and presumably IP-induced Ca2+ release may function as the transducing mechanism for cholinergic contraction of tracheal smooth muscle through the activation of M3 receptors.

Full text

PDF
613

Selected References

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

  1. Ashkenazi A., Winslow J. W., Peralta E. G., Peterson G. L., Schimerlik M. I., Capon D. J., Ramachandran J. An M2 muscarinic receptor subtype coupled to both adenylyl cyclase and phosphoinositide turnover. Science. 1987 Oct 30;238(4827):672–675. doi: 10.1126/science.2823384. [DOI] [PubMed] [Google Scholar]
  2. Barlow R. B., Berry K. J., Glenton P. A., Nilolaou N. M., Soh K. S. A comparison of affinity constants for muscarine-sensitive acetylcholine receptors in guinea-pig atrial pacemaker cells at 29 degrees C and in ileum at 29 degrees C and 37 degrees C. Br J Pharmacol. 1976 Dec;58(4):613–620. doi: 10.1111/j.1476-5381.1976.tb08631.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. 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]
  4. Berridge M. J., Dawson R. M., Downes C. P., Heslop J. P., Irvine R. F. Changes in the levels of inositol phosphates after agonist-dependent hydrolysis of membrane phosphoinositides. Biochem J. 1983 May 15;212(2):473–482. doi: 10.1042/bj2120473. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Berridge M. J., Heslop J. P., Irvine R. F., Brown K. D. Inositol trisphosphate formation and calcium mobilization in Swiss 3T3 cells in response to platelet-derived growth factor. Biochem J. 1984 Aug 15;222(1):195–201. doi: 10.1042/bj2220195. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Birdsall N. J., Burgen A. S., Hulme E. C. The binding of agonists to brain muscarinic receptors. Mol Pharmacol. 1978 Sep;14(5):723–736. [PubMed] [Google Scholar]
  7. Bonner T. I. The molecular basis of muscarinic receptor diversity. Trends Neurosci. 1989 Apr;12(4):148–151. doi: 10.1016/0166-2236(89)90054-4. [DOI] [PubMed] [Google Scholar]
  8. Bonner T. I., Young A. C., Brann M. R., Buckley N. J. Cloning and expression of the human and rat m5 muscarinic acetylcholine receptor genes. Neuron. 1988 Jul;1(5):403–410. doi: 10.1016/0896-6273(88)90190-0. [DOI] [PubMed] [Google Scholar]
  9. Brown J. H., Brown S. L. Agonists differentiate muscarinic receptors that inhibit cyclic AMP formation from those that stimulate phosphoinositide metabolism. J Biol Chem. 1984 Mar 25;259(6):3777–3781. [PubMed] [Google Scholar]
  10. Buckley N. J., Bonner T. I., Buckley C. M., Brann M. R. Antagonist binding properties of five cloned muscarinic receptors expressed in CHO-K1 cells. Mol Pharmacol. 1989 Apr;35(4):469–476. [PubMed] [Google Scholar]
  11. Candell L. M., Yun S. H., Tran L. L., Ehlert F. J. Differential coupling of subtypes of the muscarinic receptor to adenylate cyclase and phosphoinositide hydrolysis in the longitudinal muscle of the rat ileum. Mol Pharmacol. 1990 Nov;38(5):689–697. [PubMed] [Google Scholar]
  12. Doods H. N., Mathy M. J., Davidesko D., van Charldorp K. J., de Jonge A., van Zwieten P. A. Selectivity of muscarinic antagonists in radioligand and in vivo experiments for the putative M1, M2 and M3 receptors. J Pharmacol Exp Ther. 1987 Jul;242(1):257–262. [PubMed] [Google Scholar]
  13. Farley J. M., Miles P. R. Role of depolarization in acetylcholine-induced contractions of dog trachealis muscle. J Pharmacol Exp Ther. 1977 Apr;201(1):199–205. [PubMed] [Google Scholar]
  14. Giachetti A., Micheletti R., Montagna E. Cardioselective profile of AF-DX 116, a muscarine M2 receptor antagonist. Life Sci. 1986 May 5;38(18):1663–1672. doi: 10.1016/0024-3205(86)90410-8. [DOI] [PubMed] [Google Scholar]
  15. Giraldo E., Micheletti R., Montagna E., Giachetti A., Viganò M. A., Ladinsky H., Melchiorre C. Binding and functional characterization of the cardioselective muscarinic antagonist methoctramine. J Pharmacol Exp Ther. 1988 Mar;244(3):1016–1020. [PubMed] [Google Scholar]
  16. Gown A. M., Vogel A. M., Gordon D., Lu P. L. A smooth muscle-specific monoclonal antibody recognizes smooth muscle actin isozymes. J Cell Biol. 1985 Mar;100(3):807–813. doi: 10.1083/jcb.100.3.807. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Grandordy B. M., Cuss F. M., Sampson A. S., Palmer J. B., Barnes P. J. Phosphatidylinositol response to cholinergic agonists in airway smooth muscle: relationship to contraction and muscarinic receptor occupancy. J Pharmacol Exp Ther. 1986 Jul;238(1):273–279. [PubMed] [Google Scholar]
  18. Hammer R., Berrie C. P., Birdsall N. J., Burgen A. S., Hulme E. C. Pirenzepine distinguishes between different subclasses of muscarinic receptors. Nature. 1980 Jan 3;283(5742):90–92. doi: 10.1038/283090a0. [DOI] [PubMed] [Google Scholar]
  19. Harden T. K., Heng M. M., Brown J. H. Receptor reserve in the calcium-dependent cyclic AMP response of astrocytoma cells to muscarinic receptor stimulation: demonstration by agonist-induced desensitization, receptor inactivation, and phorbol ester treatment. Mol Pharmacol. 1986 Sep;30(3):200–206. [PubMed] [Google Scholar]
  20. 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]
  21. Hulme E. C., Birdsall N. J., Buckley N. J. Muscarinic receptor subtypes. Annu Rev Pharmacol Toxicol. 1990;30:633–673. doi: 10.1146/annurev.pa.30.040190.003221. [DOI] [PubMed] [Google Scholar]
  22. Melchiorre C., Angeli P., Lambrecht G., Mutschler E., Picchio M. T., Wess J. Antimuscarinic action of methoctramine, a new cardioselective M-2 muscarinic receptor antagonist, alone and in combination with atropine and gallamine. Eur J Pharmacol. 1987 Dec 1;144(2):117–124. doi: 10.1016/0014-2999(87)90509-7. [DOI] [PubMed] [Google Scholar]
  23. Micheletti R., Montagna E., Giachetti A. AF-DX 116, a cardioselective muscarinic antagonist. J Pharmacol Exp Ther. 1987 May;241(2):628–634. [PubMed] [Google Scholar]
  24. Nathanson N. M. Molecular properties of the muscarinic acetylcholine receptor. Annu Rev Neurosci. 1987;10:195–236. doi: 10.1146/annurev.ne.10.030187.001211. [DOI] [PubMed] [Google Scholar]
  25. Peralta E. G., Ashkenazi A., Winslow J. W., Ramachandran J., Capon D. J. Differential regulation of PI hydrolysis and adenylyl cyclase by muscarinic receptor subtypes. Nature. 1988 Aug 4;334(6181):434–437. doi: 10.1038/334434a0. [DOI] [PubMed] [Google Scholar]
  26. Roffel A. F., Elzinga C. R., Van Amsterdam R. G., De Zeeuw R. A., Zaagsma J. Muscarinic M2 receptors in bovine tracheal smooth muscle: discrepancies between binding and function. Eur J Pharmacol. 1988 Aug 9;153(1):73–82. doi: 10.1016/0014-2999(88)90589-4. [DOI] [PubMed] [Google Scholar]
  27. 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]
  28. Sankary R. M., Jones C. A., Madison J. M., Brown J. K. Muscarinic cholinergic inhibition of cyclic AMP accumulation in airway smooth muscle. Role of a pertussis toxin-sensitive protein. Am Rev Respir Dis. 1988 Jul;138(1):145–150. doi: 10.1164/ajrccm/138.1.145. [DOI] [PubMed] [Google Scholar]
  29. Shapiro R. A., Scherer N. M., Habecker B. A., Subers E. M., Nathanson N. M. Isolation, sequence, and functional expression of the mouse M1 muscarinic acetylcholine receptor gene. J Biol Chem. 1988 Dec 5;263(34):18397–18403. [PubMed] [Google Scholar]

Articles from British Journal of Pharmacology are provided here courtesy of The British Pharmacological Society

RESOURCES