Skip to main content
SpringerLink
Log in

Use of M1–M5 Muscarinic Receptor Knockout Mice as Novel Tools to Delineate the Physiological Roles of the Muscarinic Cholinergic System

  • Published:
Neurochemical Research Aims and scope Submit manuscript

Abstract

In this review we report recent findings on the physiological role of the five known muscarinic acetylcholine receptors (mAChRs) as shown by gene targeting technology. Using knockout mice for each mAChRs subtype, the role of mAChRs subtypes in a number of physiological functions was confirmed and new activities were discovered. The M1 mAChRs modulate neurotransmitter signaling in cortex and hippocampus. The M3 mAChRs are involved in exocrine gland secretion, smooth muscle contractility, pupil dilation, food intake, and weight gain. The role of the M5 mAChRs involves modulation of central dopamine function and the tone of cerebral blood vessels. mAChRs of the M2 subtype mediate muscarinic agonist-induced bradycardia, tremor, hypothermia, and autoinhibition of release in several brain regions. M4 mAChRs modulate dopamine activity in motor tracts and act as inhibitory autoreceptors in striatum. Thus, as elucidated by gene targeting technology, mAChRs have widespread and manifold functions in the periphery and brain.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

REFERENCES

  1. Gomeza, J., Shannon, H. E., Kostenis, E., Felder, C., Zhang, L., Brodkin, J., Grinberg, A., Sheng, H., and Wess, J. 1999a. Pronounced pharmacological deficits in M2 muscarinic acetylcholine receptor knockout mice. Proc. Natl. Acad. Sci. USA 96:1692–1697.

    PubMed  Google Scholar 

  2. Bymaster, F. P., Shannon, H. E., Rasmussen, K., DeLapp, N. W., Ward, J. S., Calligaro, D. O., Mitch, C. H., Whitesitt, C., Ludvigsen, T. S., Sheardown, M., Swedberg, M., Rasmussen, T., Olesen, P. H., Jeppesen, L., Sauerberg, P., and Fink-Jensen, A. 1999. Potential role of muscarinic receptors in schizophrenia. Life Sci. 64:527–534.

    PubMed  Google Scholar 

  3. Felder, C. C., Bymaster, F. P., Ward, J., and DeLapp, N. 2000. Therapeutic opportunities for muscarinic receptors in the central nervous system. J. Med. Chem. 43:4333–4353.

    PubMed  Google Scholar 

  4. Eglen, R. M., Choppin, A., Dillon, M. P., and Hegde, S. 1999. Muscarinic receptor ligands and their therapeutic potential. Curr. Opin. Chem. Biol. 3:426–432.

    PubMed  Google Scholar 

  5. Cutler, N. R. and Sramek, J. J. 1995. Muscarinic M1-receptor agonists: Potential in the treatment of Alzheimer's disease. CNS Drugs 3:467–481.

    Google Scholar 

  6. Gomeza, J., Zhang, L., Kostenis, E., Felder, C., Bymaster, F., Brodkin, J., Shannon, H., Xia, B., Deng, C.-X., and Wess, J. 1999b. Enhancement of D1 dopamine receptor-mediated locomotor stimulation in M4 muscarinic acetylcholine receptor knockout mice. Proc. Natl. Acad. USA 96:10483–10488.

    Google Scholar 

  7. Miyakawa, T., Yamada, M., Duttaroy, A., and Wess, J. 2001. Hyperactivity and intact hippocampus-dependent learning in mice lacking the m1 muscarinic acetylcholine receptor. J. Neuorsci. 21:5239–5250.

    Google Scholar 

  8. Yamada, M., Miyakawa, T., Duttaroy, A., Yamanaka, A., Moriguchi, T., Makita, R., Ogawa, M., Chou, C. J., Xia, B., Crawley, J. N., Felder, C. C., Den, C.-X., and Wess, J. 2001a. Mice lacking the M3 muscarinic acetylcholine receptor are hypophagic and lean. Nature 410:207–212.

    PubMed  Google Scholar 

  9. Yamada, M., Lamping, K. G., Duttaroy, A., Zhang, W., Cui, Y., Bymaster, F. P., McKinzie, D. L., Felder, C. C., Deng, C.-X., Faraci, F. M., and Wess, J. 2001b. Cholinergic dilation of cerebral blood vessels is abolished in M5 muscarinic acetylcholine receptor knockout mice. Proc. Natl. Acad. Sci. USA 98:14096–14101.

    PubMed  Google Scholar 

  10. Levey, A. I. 1993. Immunological localization of m1-m5 muscarinic acetylcholine receptors in peripheral tissues and brain. Life Sci. 52:441–448.

    PubMed  Google Scholar 

  11. Caulfield, M. P. and Birdsall, N. J. M. 1998. International Union of Pharmacology: XVII. Classification of muscarinic acetylcholine receptors. Pharmacol. Rev. 50 279-290.

    PubMed  Google Scholar 

  12. Roszkowski, A. 1961. An unusual type of sympathetic ganglionic stimulant. J. Pharmacol. Exp. Ther. 132:156–170.

    PubMed  Google Scholar 

  13. Hardouin, S. N., Richmond, K. N., Zimmerman, A., Hamilton, S. E., Feigl, E. O., and Nathanson, N. M. 2002. Altered cardiovascular responses in mice lacking the M1 muscarinic acetylcholine receptor. J. Pharmacol. Exp. Ther. 301:129–137.

    PubMed  Google Scholar 

  14. Hamilton, S. E., Loose, M. D., Qi, M., Levey, A. I., Hille, B., McKnight, G. S., Idzerda, R. L., and Nathanson, N. M. 1997. Disruption of the m1 receptor gene ablates muscarinic receptor-dependent M current regulation and seizure activity in mice. Proc. Natl. Acad. Sci. USA 94:13311–13316.

    PubMed  Google Scholar 

  15. Bymaster, F. P., Carter, P. A., Yamada M., Gomeza, J., Wess, J., Hamilton, S. E., Nathanson, N. M., McKinzie, D., and Felder, C. C. 2002. Role of specific muscarinic receptor subtypes in cholinergic parasympathomimetic responses, in vivo phosphoinositide hydrolysis, and pilocarpine-induced seizure activity. Eur. J. Neuroscience, Submitted.

  16. Felder, C. C., Porter, A. C., Skillman, T. L., Zhang, L., Bymaster, F. P., Nathanson, N. M., Hamilton, S. E., Gomeza, J., Wess, J., and McKinzie, D. L. 2001. Elucidating the role of muscarinic receptors in psychosis. Life Sci. 68:2605–2613.

    PubMed  Google Scholar 

  17. Porter, A. C., Bymaster, F. P., DeLapp, N. W., Yamada, M., Wess, J., Hamilton, S. E., Nathanson, N. M., and Felder, C. C. 2002. M1 muscarinic receptor signaling in mouse hippocampus and cortex. Brain Res. 944:82–89.

    PubMed  Google Scholar 

  18. Hamilton, S. E. and Nathanson, N. M. 2001. The M1 receptor is required for muscarinic activation of mitogen-activated protein (MAP) kinase in murine cerebral cortical neurons. J. Biol. Chem. 276:15850–15853.

    PubMed  Google Scholar 

  19. Berkeley, J. L., Gomeza, J., Wess, J., Hamilton, S. E., Nathanson, N. M., and Levey, A. I. 2001. M1 Muscarinic acetylcholine receptors activate extracellular signal-regulated kinase in CA1 pyramidal neurons in mouse hippocampal slices. Mol. Cell Neurosci. 18:512–524.

    PubMed  Google Scholar 

  20. Sarter, M. and Bruno, J. P. 1997. Cognitive functions of cortical acetylcholine: Toward a unifying hypothesis. Brain Res. Brain Res. Rev. 23:28–46.

    PubMed  Google Scholar 

  21. Gerber, D. J., Sotnikova, T. D., Gainetdinov, R. R., Huang, S. H. and Caron, M. G. 2001. Hyperactivity, elevated dopaminergic transmission, and response to amphetamine in M1 muscarinic acetylcholine receptor-deficient mice. Proc. Natl. Acad. Sci. USA 98:15312–15317.

    PubMed  Google Scholar 

  22. Greene, S. J., Felder, C. C., Hamilton, S. E., Nathanson, N. M., and Gannon, K. S. 2001. Analyses of spatial learning and activity in muscarinic M1 receptor knockout mice: Evidence for a cognitive deficit. Soc. Neurosci. Abstrs. 27:prog #79.12.

  23. Anagnostaras, S. G., Murphy, G. G., Sage J. R., Hamilton, S. E., Nathanson, N. M., and Silva, A. J. 2000. Learning and memory in acetylcholine muscarinic M1 receptor knockout mice. Soc. Neurosci. Abstr. 26:1509.

    Google Scholar 

  24. Caulfield, M. P. 1993. Muscrinic receptors characterization, coupling and function. Pharmacol. Ther. 58 319–379.

    PubMed  Google Scholar 

  25. Matsui, M., Motomura, D., Karasawa, H., Fujikawa, T., Jiang, J., Komiya, Y., Takahashi, S.-I., and Taketo, M. M. 2000. Multiple functional defects in peripheral autonomic organs in mice lacking muscarinic acetylcholine receptor gene for the M3 subtype. Proc. Natl. Acad. Sci. USA 97:9579–9584.

    PubMed  Google Scholar 

  26. Stengel, P. W., Yamada, M., Wess, J., and Cohen, M. L. 2002. M3 receptor knockout mice: Muscarinic receptor function in atria, stomach fundus, urinary bladder and trachea in vitro. Am. J. Physiol. 282:R1443–R1449.

    Google Scholar 

  27. Gil, D. W., Krauss, H. A., Bogardus, A. M., and WoldeMussie, E. 1997. Muscarinic receptor subtypes in human iris-ciliary body measured by immunoprecipitation. Invest. Ophthalmol. Vis. Sci. 38:1434–1442.

    PubMed  Google Scholar 

  28. Ishizaka, N., Noda, M., Yokoyama, S., Kawasaki, K., Yamamoto, M., and Higashida, H. 1998. Muscarinic acetylcholine receptor subtypes in the human iris. Brain Res. 787:344–347.

    PubMed  Google Scholar 

  29. Phillips, J. K., Vidovic, M., and Hill, C. E. 1997. Variation in mRNA expression of alpha-adrenergic, neurokinin and muscarinic receptors amongst four arteries of the rat. J. Auton. Nerv. Syst. 62:85–93.

    PubMed  Google Scholar 

  30. Elhusseiny, A., Cohen, Z., Olivier, A., Stanimirovic, D. B., and Hamel, E. 1999. Functional acetylcholine muscarinic receptor subtypes in human brain microcirculation: identification and cellular localization. J. Cereb. Blood Flow Metab. 19:794–802.

    PubMed  Google Scholar 

  31. Weiner, D. M., Levey, A. I., and Brann, M. R. 1990. Expression of muscarinic acetylcholine and dopamine receptor mRNAs in rat basal ganglia. Proc. Natl. Acad. Sci. USA 87:7050–7054.

    PubMed  Google Scholar 

  32. Yeomans, J., Forster, G., and Blaha, C. 2001. M5 muscarinic receptors are needed for slow activation of dopamine neurons and for rewarding brain stimulation. Life Sci. 68:2449–2456.

    Google Scholar 

  33. Stengel, P. W., Gomeza, J., Wess, J., and Cohen, M. L. 2000. M2 and M4 receptor knockout mice: muscarinic receptor function in cardiac and smooth muscle in vitro. J. Pharmacol. Exp. Ther. 292:877–885.

    PubMed  Google Scholar 

  34. Marchi, M. and Raiteri, M. 1985. On the presence in the cerebral cortex of muscarinic receptor subtypes which differ in neuronal localization, function and pharmacological properties. J. Pharmacol. Exp. Ther. 235:230–233.

    PubMed  Google Scholar 

  35. Damsma, G., de Boer, P., Westerink, B. H., and Fibiger, H. C. 1990. Dopaminergic regulation of striatal cholinergic interneurons: An in vivo microdialysis study. Naunyn Schmiedebergs Arch. Pharmacol. 342:523–527.

    PubMed  Google Scholar 

  36. Zhang, W., Basile, A. S., Gomeza, J., Volpicelli, L. A., Levey, A. I., and Wess, J. 2002. Characterization of central inhibitory muscarinic autoreceptors by the use of muscarinic acetylcholine receptor knock-out mice. J. Neurosci. 22:1709–1717.

    PubMed  Google Scholar 

  37. Swedberg, M. D., Sheardown, M. J., Sauerberg, P., Olesen, P. H., Suzdak, P. D., Hansen, K. T., Bymaster, F. P., Ward, J. S., Mitch, C. H., Calligaro, D. O., Delapp, N. W., and Shannon, H. E. 1997. Butylthio[2.2.2] (NNC 11–1053/LY297802): An orally active muscarinic agonist analgesic. J. Pharmacol. Exp. Ther. 281:876–883.

    PubMed  Google Scholar 

  38. Hemrick-Luecke, S. K., Felder, C. C., Evans, D. E., Wess, J., and Bymaster, F. P. 2000. Effect of BuTAC on the elevation of serum corticosterone concentrations in M2 and M4 muscarinic acetylcholine receptor knockout mice. Soc. Neurosci. Abstr. 26:1644.

    Google Scholar 

  39. Hemrick-Luecke, S. K., Bymaster, F. P., Evans, D. C., Wess, J., and Felder, C. C. 2002. Muscarinic agonist-mediated increases in serum corticosterone levels are abolished in m2 muscarinic acetylcholine receptor knockout mice. J. Pharmacol. Exp. Ther. 303:99-103.

    PubMed  Google Scholar 

  40. Kilbinger, H., Von Bardeleben, R. S., Siefken, H., and Wolf, D. 1995. Prejunctional muscarinic receptors regulating neurotransmitter release in airways. Life Sci. 56:981–988.

    PubMed  Google Scholar 

  41. Bernard, V., Normand, E., and Bloch, B. 1992. Phenotypical characterization of the rat striatal neurons expressing muscarinic receptor genes. J. Neurosci. 12:3591–3600.

    PubMed  Google Scholar 

  42. Duttaroy, A., Gomeza, J., Gan, J.-W., Basile, A. S., Harman, W. D., Smith, P. L., Felder, C. C., and Wess, J. 2000. Analysis of muscarinic agonist-induced analgesia by the use of receptor knockout mice. Soc. Neurosci. Abstr. 26:1644.

    Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana, 46285

    Frank P. Bymaster, David L. McKinzie & Christian C. Felder

  2. Laboratory of Bioorganic Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, Maryland, 20892

    Jürgen Wess

Authors
  1. Frank P. Bymaster
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. David L. McKinzie
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Christian C. Felder
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Jürgen Wess
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Frank P. Bymaster.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Bymaster, F.P., McKinzie, D.L., Felder, C.C. et al. Use of M1–M5 Muscarinic Receptor Knockout Mice as Novel Tools to Delineate the Physiological Roles of the Muscarinic Cholinergic System. Neurochem Res 28, 437–442 (2003). https://doi.org/10.1023/A:1022844517200

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1023/A:1022844517200

Search

Navigation