Molecular Biology, Pharmacology, and Brain Distribution of Subtypes of the Muscarinic Receptor


F. J. Ehlert
Department of Pharmacology
College of Medicine
University of California
Irvine, California 92717.

W. R. Roeske
Department of Medicine
College of Medicine
University of Arizona
Tucson, Arizona 85724.

H. I. Yamamura
Department of Pharmacology
College of Medicine
University of Arizona
Tucson, Arizona 85724.


1. Ashkenazi A, Winslow JW, Peralta EG, Peterson GL, Schimerlik MI, Capon DJ, Ramachandran J. An M2 muscarinic receptor subtype coupled to both adenylyl cyclase and phosphoinositide turnover. Science 1987;238:672675.

2. Barlow RB, Berry KJ, Glenton PAM, Nikolaou NM, Soh KS. A comparison of affinity constants for muscarine-sensitive acetylcholine receptors in guinea-pig atrial pacemaker cells at 29C and in ileum at 29C and 37C. Br J Pharmacol 1976;58:613620.

3. Baumgold J, Drobnick A. An agonist that is selective for adenylate cyclase-coupled muscarinic receptors. Mol Pharmacol 1989; 36:465470.

4. Birdsall NJM, Chan S-C, Eveleigh P, Hulme EC, Miller KW. The modes of binding of ligands to cardiac muscarinic receptors. Trends Pharmacol Sci 1990; (suppl):3134.

5. Bloom JW, Halonen M, Yamamura HI. Characterization of muscarinic cholinergic receptor subtypes in human peripheral lung. Mol Pharmacol 1988;244:625632.

6. Bonner TI, Buckley NJ, Young AC, Brann MR. Identification of a family of muscarinic acetylcholine receptor genes. Science 1987;237:527532.

7. Brann MR, Klimkowski VJ, Ellis J. Structure/function relationships of muscarinic acetylcholine receptors. Life Sci 1993;52:405412.

8. Buckley NJ, Bonner TI, Brann MR. Localization of a family of muscarinic receptor mRNAs in rat brain. J Neurosci 1988; 8(12):46464652.

9. Buckley NJ, Bonner TI, Buckley CM, Brann MR. Antagonist binding properties of five cloned muscarinic receptors expressed in CHO-K1 cells. Mol Pharmacol 1989;35:469476.

10. Burgen ASV. The role of ionic interactions at the muscarinic receptor. Br J Pharmacol 1965;25:47.

11. Candell LM, Yun SH, Tran LLP, Ehlert FJ. 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;38:689697.

12. Clark AL, Mitchelson F. The inhibitory effect of gallamine on muscarinic receptors. Br J Pharmacol 1976;58:323331.

13. Dale HH. The action of certain esters and ethers of choline, and their relation to muscarine. J Pharmacol Exp Ther 1914;6:147190.

14. Delmendo RE, Michel AD, Whiting RL. Affinity of muscarinic receptor antagonists for three putative muscarinic receptor binding sites. Br J Pharmacol 1989;96:457464.

15. Dörje F, Wess J, Lambrecht G, Tacke R, Mutschler E, Brann MR. Antagonist binding profiles of five cloned human muscarinic receptor subtypes. J Pharmacol Exp Ther 1991;256:727733.

16. Ehlert FJ. The relationship between muscarinic receptor occupancy and adenylate cyclase inhibition in the rabbit myocardium. Mol Pharmacol 1985;28:410421.

17. Ehlert FJ. Estimation of the affinities of allosteric ligands using radioligand binding and pharmacological null methods. Mol Pharmacol 1988;33:187194.

18. Ehlert FJ, Delen FM. Influence of pH on the binding of scopolamine and N-methylscopolamine to muscarinic receptors in the corpus striatum and heart of rats. Mol Pharmacol 1990;38:143147.

19. Ehlert FJ, Delen FM, Yun SH, Friedman DJ, Self DW. Coupling of subtypes of the muscarinic receptor to adenylate cyclase in the corpus striatum and heart. J Pharmacol Exp Ther 1989;251:660671.

20. Ehlert FJ, Roeske WR, Yamamura HI. Regulation of muscarinic receptor binding by guanine nucleotides and N-ethylmaleimide. J Supramol Struct 1980;14:149162.

21. Ehlert FJ, Tran LLP. Regional distribution of M1, M2 and non-M1, non-M2 subtypes of muscarinic binding sites in rat brain. J Pharmacol Exp Ther 1990;255:11481157.

22. Eltze M. Muscarinic M1- and M2-receptors mediating opposite effects on neuromuscular transmission in rabbit vas deferens. Eur J Pharmacol 1988;151:205221.

23. Eltze M, Gmelin G, Wess J, Strohmann C, Tacke R, Mutschler E, Lambrecht G. Presynaptic muscarinic receptors mediating inhibition of neurogenic contractions in rabbit vas deferens are of the ganglionic M1-type. Eur J Pharmacol 1988;158:233242.

24. England BP, Ackerman MS, Barrett RW. A chimeric D2 dopamine/m1 muscarinic receptor with D2 binding specificity mobilizes intracellular calcium in response to dopamine. FEBS Lett 1991;279:8790.

25. Findlay JBC, Pappin DJC. The opsin family of proteins. Biochem J 1986;238:625642.

26. Fraser CM, Wang C-D, Robinson DA, Gocayne JD, Venter JC. Site-directed mutagenesis of m1 muscarinic acetylcholine receptors: conserved aspartic acids play important roles in receptor function. Mol Pharmacol 1989;36:840847.

27. Fryer AD, El-Fakahany EE. Identification of three muscarinic receptor subtypes in rat lung using binding studies with selective antagonists. Life Sci 1990;47:611618.

28. Gao B, Gilman AG. Cloning and expression of a widely distributed (type IV) adenylyl cyclase. Proc Natl Acad Sci USA 1991; 88:1017810182.

29. Gerstin EH, Luong T, Ehlert FJ. Heparin, dextran and trypan blue allosterically modulate M2 muscarinic receptor binding properties and interfere with receptor-mediated inhibition of adenylate cyclase. J Pharmacol Exp Ther 1992;263:910917.

30. Giachetti A, Micheletti R, Montagna E. Cardioselective profile of AF-DX 116, a muscarine M2 receptor antagonist. Life Sci 1986;38:16631672.

31. Gil DW, Wolfe BB. Pirenzepine distinguishes between muscarinic receptor-mediated phosphoinositide breakdown and inhibition of adenylate cyclase. Mol Pharmacol 1985;232:608616.

32. Giraldo E, Hammer R, Ladinsky H. Distribution of muscarinic receptor subtypes in rat brain as determined in binding studies with AF-DX 116 and pirenzepine. Life Sci 40:833840.

33. Haga K, Haga T. Purification of the muscarinic acetylcholine receptor from porcine brain. J Biol Chem 1985;260:79277935.

34. Hammer R, Berrie CP, Birdsall NJM, Burgen ASV, Hulme EC. Pirenzepine distinguishes between different subclasses of muscarinic receptors. Nature 1980;283:9092.

35. Hammer R, Giachetti A. Muscarinic receptor subtypes: M1 and M2 biochemical and functional characterization. Life Sci 1982; 31:29912998.

36. Hanin I, Jenden DJ, Cho AK. The influence of pH on the muscarinic action of oxotremorine, arecoline, pilocarpine, and their quaternary ammonium analogues. Mol Pharmacol 1966;2:352359.

37. Hu J, El-Fakahany EE. Selectivity of McN-A-343 in stimulating phosphoinositide hydrolysis mediated by M1 muscarinic receptors. Mol Pharmacol 1990;38:895903.

38. Hulme EC, Birdsall NJM, Buckley NJ. Muscarinic receptor subtypes. Annu Rev Pharmacol Toxicol 1990;30:633673.

39. Hulme EC, Curtis CAM, Wheatley M, Aitken A, Harris AC. Localization and structure of the muscarinic receptor ligand binding site. Trends Pharmacol Sci 1990; (Suppl):2225.

40. Jones SVP. Muscarinic receptor subtypes: modulation of ion channels. Life Sci 1993;52:457464.

41. Kashihara K, Varga EV, Waite SL, Roeske WR, Yamamura HI. Cloning of the rat M3, M4 and M5 muscarinic acetylcholine receptor genes by the polymerase chain reaction (PCT) and the pharmacological characterization of the expressed genes. Life Sci 1992;51:955971.

42. Kubo T, Fukuda K, Mikami A, Maeda A, Takahashi H, Mishina M, Haga T, Haga K, Ichiyama A, Kangawa K, Kojima M, Matsuo H, Hirose T, Numa S. Cloning, sequencing and expression of complementary DNA encoding the muscarinic acetylcholine receptor. Nature 1986;323:411416.

43. Kubo T, Maeda A, Sugimoto K, et al. Primary structure of porcine cardiac muscarinic acetylcholine receptor deduced from the cDNA sequence. FEBS Lett 1986;209:367372.

44. Lai J, Mei L, Roeske WR, Chung F-Z, Yamamura HI, Venter JC. The cloned murine M1 muscarinic receptor is associated with the hydrolysis of phosphatidylinositols in transfected murine B82 cells. Life Sci 1988;42:24892502.

45. Lai J, Nunan L, Waite SL, Ma S-W, Bloom JW, Roeske WR, Yamamura HI. Chimeric M1/M2 Muscarinic receptors: correlation of ligand selectivity and functional coupling with structural modifications. J Pharmacol Exp Ther 1992;262:173180.

46. Lai J, Waite SL, Bloom JW, Yamamura HI, Roeske WR. The m2 muscarinic acetylcholine receptors are coupled to multiple signaling pathways via pertussis toxin-sensitive guanine nucleotide regulatory proteins. J Pharmacol Exp Ther 1991;258:938944.

47. Lambrecht G, Feifel R, Wagner-Röder M, Strohmann C, Zilch H, Tacke R, Waelbroeck M, Christophe J, Boddeke H, Mutschler E. Affinity profiles of hexahydro-sila-difenidol analogues at muscarinic receptor subtypes. Eur J Pharmacol 1989;168:7180.

48. Lazareno S, Buckley NJ, Roberts FF. Characterization of muscarinic M4 binding sites in rabbit lung, chicken heart, and NG108-15 cells. Mol Pharmacol 1990;38:805815.

49. Lazareno S, Farries T, Birdsall NJM. Pharmacological characterization of guanine nucleotide exchange reactions in membranes from CHO cells stably transfected with human muscarinic receptors M1-M4. Life Sci 1993;52:449456.

50. Lefkowitz RJ, Hoffman BB, Taylor P. Neurohumoral transmission: the autonomic and somatic motor nervous systems. In: Gilman AG, Rall TW, Nies AS, Taylor P, eds. The pharmacological basis of therapeutics. New York: Pergamon Press, 1990;84121.

51. Levey AI, Kitt CA, Simonds WF, Price DL, Brann MR. Identification and localization of muscarinic acetylcholine receptor proteins in brain with subtype-specific antibodies. J Neurosci 1991;11:32183226.

52. Li M, Yasuda RP, Wall SJ, Wellstein A, Wolfe BB. Distribution of m2 muscarinic receptors in rat brain using antisera selective for m2 receptors. Mol Pharmacol 1991;40:2835.

53. Liao C-F, Schilling WP, Birnbaumer M, Birnbaumer L. Cellular responses to stimulation of the M5 muscarinic acetylcholine receptor as seen in murine L cells. J Biol Chem 1990;265:1127311284.

54. Liao C-F, Themmen APN, Joho R, Barberis C, Birnbaumer M, Birnbaumer L. Molecular cloning and expression of a fifth muscarinic acetylcholine receptor. J Biol Chem 1989;264:73287337.

55. Maeda A, Kubo T, Mishina M, Numa S. Tissue distribution of mRNAs encoding muscarinic acetylcholine receptor subtypes. FEBS Lett 1988;239:339342.

56. Matsuo Y, Seki A. Actions of pirenzepine dihydrochloride (LS-519 Cl) on gastric juice secretion, gastric motility and experimental gastric ulcer. Arzneimittelforsch 1979;29:10281035.

57. Mei L, Lai J, Roeske WR, Fraser CM, Venter JC, Yamamura HI. Pharmacological characterization of the M1 muscarinic receptors expressed in murine fibroblast B82 cells. J Pharmacol Exp Ther 1989;248:661670.

58. Olianas MC, Onali P. Muscarinic stimulation of adenylate cyclase activity of rat olfactory bulb. II Characterization of the antagonist sensitivity and comparison with muscarinic inhibitions of the enzyme in striatum and heart. J Pharmacol Exp Ther 1991;259:680686.

59. Pedder EK, Eveleigh P, Poyner D, Hulme EC, Birdsall NJM. Modulation of the structure-binding relationships of antagonists for muscarinic acetylcholine receptor subtypes. Br J Pharmacol 1991; 103:15611567.

60. Peralta EG, Ashkenazi A, Winslow JW, Smith DH, Ramachandran J, Capon DJ. Distinct primary structures, ligand-binding properties and tissue-specific expression of four human muscarinic acetylcholine receptors. EMBO J 1987;6:39233929.

61. Peralta EG, Ashkenazi A, Winslow JW, Ramachandran J, Capon DJ. Differential regulation of PI hydrolysis and adenylyl cyclase by muscarinic receptor subtypes. Nature 1988;334:434437.

62. Peralta EG, Winslow JW, Peterson GL, Smith DH, Ashkenazi A, Ramachandran J, Schimerlik MI, Capon DJ. Primary structure and biochemical properties of an M2 muscarinic receptor. Science 1987;236:600605.

63. Potter LT, Hanchett-Valentine H, Liang J-S, Max SI, Purkerson SL, Silberberg HA, Strauss WL. m1-Toxin. Life Sci 1993;52:433440.

64. Riker WF, Wescoe WC. The pharmacology of flaxedil with observations on certain analogs. Ann NY Acad Sci 1951;54:373394.

65. Roskowski AP. An unusual type of sympathetic ganglionic stimulant. J Pharmacol Exp Ther 1961;132:156170.

66. Smith TD, Annis SJ, Ehlert FJ, Leslie FM. N-[3H]Methylscopolamine labeling of non-M1, non-M2 muscarinic receptor binding sites in rat brain. J Pharmacol Exp Ther 1990; 256:11731181.

67. Stockton JM, Birdsall NJM, Burgen ASV, Hulme EC. Modification of the binding properties of muscarinic receptors by gallamine. Mol Pharmacol 1982;23:551557.

68. Tang W-J, Gilman AG. Type-specific regulation of adenylyl cyclase by G protein bg subunits. Science 1991;254:15001503.

69. Thomas EA, Baker SA, Ehlert FJ. Functional role for the M2 muscarinic receptor in smooth muscle of guinea pig ileum. Mol Pharmacol 1993;44:102110.

70. Waelbroeck M, Gillard M, Robberecht P, Christophe J. Kinetic studies of [3H]N-methylscopolamine binding to muscarinic receptors in rat central nervous system: evidence for the existence of three classes of binding sites. Mol Pharmacol 1986;30:305314.

71. Waelbroeck M, Tastenoy M, Camus J, Christophe J. Binding of selective antagonists to four muscarinic receptors (M1 to M4) in rat forebrain. Mol Pharmacol 1990;38:267273.

72. Wall SJ, Yasuda RP, Hory F, Flagg S, Martin BM, Ginns EI, Wolfe BB. Production of antisera selective for m1 muscarinic receptors using fusion proteins: distribution of m1 receptors in rat brain. Mol Pharmacol 1991;39:643649.

73. Wall SJ, Yasuda RP, Li M, Wolfe BB. Development of an antiserum against m3 muscarinic receptors: distribution of m3 receptors in rat tissues and clonal cell lines. Mol Pharmacol 1991;40:783789.

74. Walton FA. Flaxedil: a new curarizing agent. Can Med Assoc J 1950;63:123129.

75. Wang JX, Roeske WR, Gulya K, Yamamura HI. [3H]AF-DX 116 labels subsets of muscarinic cholinergic receptors in rat cerebral cortical and cardiac membranes. Life Sci 1987;41:17511760.

76. Watson M, Yamamura HI, Roeske WR. A unique regulatory profile and regional distribution of [3H]pirenzepine binding in the rat provide evidence for distinct M1 and M2 muscarinic receptor subtypes. Life Sci 1983;32:30013011.

77. Wess J, Bonner TI, Dörje F, Brann MR. Delineation of muscarinic receptor domains conferring selectivity of coupling to guanine nucleotide-binding proteins and second messengers. Mol Pharmacol 1990;38:517523.

78. Wess J, Gdula D, Brann MR. Site-directed mutagenesis of the m3 muscarinic receptor: identification of a series of threonine and tyrosine residues involved in agonist but not antagonist binding. EMBO J 1991;10:37293734.

79. Wess J, Maggio R, Palmer JR, Vogel Z. Role of conserved threonine and tyrosine residues in acetylcholine binding and muscarinic receptor activation. J Biol Chem 1992;267:1931319319.

80. Wong SK-F, Parker EM, Ross EM. Chimeric muscarinic cholinergic b-adrenergic receptors that activate Gs in response to muscarinic agonists. J Biol Chem 1990;265:62196224.

81. Yamamura HI, Kuhar MJ, Greenberg D, Snyder SH. Muscarinic cholinergic receptor binding: regional distribution in monkey brain. Brain Res 1974;66:541546.

82. Yasuda RP, Ciesla W, Flores LR, Wall SJ, Li M, Satkus SA, Weisstein JS, Spagnola BV, Wolfe BB. Development of antisera selective for m4 and m5 muscarinic cholinergic receptors: distribution of m4 and m5 receptors in rat brain. Mol Pharmacol 1992;43:149157.

Back to Chapter

published 2000