Muscarinic Acetylcholine Receptors

  • S. V. Penelope Jones
  • Allan I. Levey
  • David M. Weiner
  • John Ellis
  • Elizabeth Novotny
  • Shua-Hua Yu
  • Frank Dorje
  • Jurgen Wess
  • Mark R. Brann
Part of the Applications of Molecular Genetics to Pharmacology book series


In 1914 Dale discovered two types of response to acetylcholine, one mimicked by muscarine and one by nicotine (Dale 1914; Dale and Ewin, 1914). This led to the subsequent discovery of nicotinic and muscarinic acetylcholine receptors. In addition to their pharmacological differences, muscarinic and nicotinic receptors can be differentiated by the mechanism and speed by which their cellular signals are transduced. Nicotinic receptors have a central pore through which sodium and potassium ions pass, resulting in depolarization of the cell membrane. Acetylcholine activates nicotinic receptors by opening the channel, and thus the response is as fast as the channel opening rate (ms). Muscarinic responses are more diverse, both hyperpolarizing and depolarizing cells by a variety of mechanisms. Muscarinic responses are also slower (on the order of 100’s of milliseconds to seconds), due to their interaction with GTP-binding proteins (G-proteins) through which the cellular response is transduced. The slowest signals involve second messengers activated via the G-proteins. Examples include inhibition of adenylyl cyclase (reducing cAMP levels), stimulation of phosphatidylinositol (PI) hydrolysis (raising inositol tris phosphate which stimulates release of calcium from cytosolic stores), and arachidonic acid metabolism. These second messengers, in turn, stimulate a wide variety of responses. For example, mobilized calcium opens calcium-dependent potassium channels, and the activities of protein kinase A and C are dependent on cAMP and PI metabolism, respectively.


Receptor Subtype Muscarinic Receptor Calcium Current Muscarinic Acetylcholine Receptor Muscarinic Agonist 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. Akiba I, Kubo T, Maeda A, Bujo H, Kakai J, Mishina M, Numa S (1988): Primary structure of porcine muscarinic acetylcholine receptor III and antagonist binding studies. FEBS Lett 235: 257–261Google Scholar
  2. Akins PT, Surmeier DJ, Kitai ST (1990): Muscarinic modulation of a transient K + conductance in rat neostriatal Neurons. Nature 344: 240–242Google Scholar
  3. Ashkenazi A, Peralta EG, Winslow JW, Ramachandran J, Capon DJ (1989a): Functionally distinct G-proteins selectively couple different receptors to PI hydrolysis in the same cell. Cell 56: 487–493Google Scholar
  4. Ashkenazi A, Ramachandran J, Capon DJ (1989b): Acetylcholine analogue stimulates DNA synthesis in brain-derived cells via specific muscarinic receptor subtypes. Nature 340: 146–150Google Scholar
  5. Baumgold J, Drobnick A (1989): An agonist that is selective for adenylate cyclase-coupled muscarinic receptors. Mol Pharmacol 36: 465–470Google Scholar
  6. Baumgold J, White T (1989): Pharmacological differences between muscarinic receptors coupled to phosphoinositide turnover and those coupled to adenylate cyclase inhibition. Biochem Pharmacol 38: 1605–1616Google Scholar
  7. Benham CD, Bolton TB, Lang RJ (1985): Acetylcholine activates an inward current in single mammalian smooth muscle cells. Nature 316: 345–347Google Scholar
  8. Benovic JL, Deblasi A, Stone WC, Caron MG, Lefkowitz RJ (1989): ß-Adrenergic receptor kinase: Primary structure delineates a multigene family. Science 246: 235–246Google Scholar
  9. Bernheim L, Beech DJ, Hille B (1991): A diffusible second messenger mediates one of the pathways coupling receptors to calcium channels in rat sympathetic Neurons. Neuron 6: 859–867Google Scholar
  10. Birdsall NJM, Hulme EC, Kromer W, Stockton JM (1987): A second drug binding site on muscarinic receptors. Fed Proc 46: 2525–2527Google Scholar
  11. Bonner TI, Buckley NJ, Young AC, Brann MR (1987): Identification of a family of muscarinic acetylcholine receptor genes. Science 237: 527–532Google Scholar
  12. Bonner TI, Young A, Brann MR, Buckley NJ (1988): Cloning and expression of the human and rat m5 muscarinic receptor genes. Neuron 1: 403–410Google Scholar
  13. Brann MR (1989): Neuronal receptors, molecular biology approaches. In: Neuroscience Year: The Yearbook of the Encyclopedia of Neuroscience, Adelman G, ed. Boston: Birkhauser, Suppl 1, pp 120–123Google Scholar
  14. Brann MR, Buckley NJ, Bonner TI (1988a): The striatum and cerebral cortex express different muscarinic receptor mRNAs. FEBS Lett 230: 90–94Google Scholar
  15. Brann MR, Buckley NJ, Jones SVP, Bonner TI (1987): Expression of a cloned muscarinic receptor in A9 L cells. Mol Pharmacol 32: 450–455Google Scholar
  16. Brann MR, Conklin BR, Dean NM, Collins RM, Bonner TI, Buckley NJ (1988b): Cloned muscarinic receptors couple to different G-proteins and second messengers. Soc Neurosci Abstr 14: 600Google Scholar
  17. Brann MR, Wess J, Jones SVP (1990): Molecular genetics of signal transduction by muscarinic acetylcholine receptors. Proceedings of 43rd symposium on “G- Proteins and Signal Transduction. ” J Gen Physiol 45: 106–115Google Scholar
  18. Breitwieser GE, Szabo G (1985): Uncoupling of cardiac muscarinic and beta-adrenergic receptors from ion channels by a guanine nucleotide analogue. Nature 317: 538–540Google Scholar
  19. Briggs CA, Cooper JR (1982): Cholinergic modulation of the release of 3H- acetylcholine from synaptasomes of the myenteric plexus. J Neurochem 38: 501–508Google Scholar
  20. Brown AM, Birnbaumer L (1990): Ionic channels and their regulation by G protein subunits. Annu Rev Physiol 52: 197–213Google Scholar
  21. Brown DA (1986): ACh and brain cells. Nature 319: 358–359Google Scholar
  22. Brown DA (1988a): M currents. In: Ion Channels Narahashi T, ed. New York and London: Plenum Press, Vol 1, pp 55–94Google Scholar
  23. Brown DA (1988b): M-currents: An update. Trends Neurosci 11: 294–299Google Scholar
  24. Brown DA (1990): G-proteins and potassium currents in Neurons. Annu Rev Physiol 52: 215–242Google Scholar
  25. Brown DA, Higashida H (1988): Inositol 1,4,5-trisphosphate and diacylglycerol mimic bradykinin effects on mouse neuroblastoma x glioma hybrid cells. J Physiol (Lond) 397: 185–207Google Scholar
  26. Brown DA, Marrion NV, Smart TG (1989): On the transduction mechanism for muscarine-induced inhibition of M-current in cultured rat sympathetic Neurons. J Physiol (Lond) 413: 469–488Google Scholar
  27. Buckley NJ, Bonner TI, Brann MR (1988): Localization of a family of muscarinic receptor mRNAs in rat brain. J Neurosci 8: 4646–4652Google Scholar
  28. Buckley NJ, Bonner TI, Buckley CM, Brann MR (1989): Antagonist binding properties of five-cloned muscarinic receptors expressed in CHO-K1 cells. Mol Pharmacol 35: 469–476Google Scholar
  29. Candell LM, Yun SH, Tran LL, Ehlert J (1990): Differential coupling of subtypes of the muscarinic receptor to adenylate cyclase and phosphoinositide hydrolysis in longitudinal muscle of the rat ileum. Mol Pharmacol 38: 689–697Google Scholar
  30. Cassell JF, McLachlan EM (1987): Muscarinic agonists block five different potassium conductances in guinea-pig sympathetic Neurons. Br J Pharmacol 91: 259–261Google Scholar
  31. Christie MJ, North RA (1988): Control of ion conductances by muscarinic receptors. Trends Pharmacol Sci [Suppl] 3: 30–34Google Scholar
  32. Clapp LH, Vivaudou MB, Walsh JJ, Singer JJ (1987): Acetylcholine increases voltage-activated calcium currents in freshly dissociated smooth muscle cells. Proc Natl Acad Sci USA 84: 2092–2096Google Scholar
  33. Clark AL, Mitchelson F (1976): The inhibitory effect of gallamine on muscarinic receptors. Br J Pharmacol 58: 323–331Google Scholar
  34. Conklin BR, Brann MR, Buckley NJ, Bonner TI, Ma AL, Felder C, Axelrod J (1989): Carbachol stimulation causes inhibition of mitogenesis and cell elongation in CHO cells transfected with muscarinic receptor genes. Trends Pharmacol Sci [Suppl] 4:Abstr 74Google Scholar
  35. Conklin BR, Brann MR, Buckley NJ, Ma AL, Bonner TI, Axelrod J (1988): Stimulation of arachidonic acid release and inhibition of mitogenesis by cloned muscarinic receptor subtypes stably expressed in A9 L cells. Proc Natl Acad Sci USA 85: 8698–8702Google Scholar
  36. Cortes R, Palacios JM (1986): Muscarinic cholinergic receptor subtypes in the rat brain. I. Quantitative autoradiographic studies. Brain Res 362: 227–238Google Scholar
  37. Curtis CAM, Wheatley M, Basal S, Birdsall NJM, Eveleigh P, Pedder EK, Poyner D, Hulme EC (1989): Propylbenzilylcholine mustard labels an acidic residue in transmembrane helix 3 of the muscarinic receptor. J Biol Chem 264: 489–495Google Scholar
  38. Dale HH (1914): The occurrence in ergot and action of acetylcholine. Proc Physiol Soc Lond p iiiGoogle Scholar
  39. Dale HH, Ewin A J (1914): Choline-esters and muscarine. Proc Physiol Soc Lond p xxivGoogle Scholar
  40. Diamont S, Schwartz S, Atlas D (1990): Potentiation of neurotransmitter release coincides with potentiation of phosphatidyl inositol turnover. A possible in vitro model for long term potentiation. Neurosci Lett 109: 140–145Google Scholar
  41. Dolphin AC (1990): G protein modulation of calcium currents in Neurons. Annu Rev Physiol 52: 243–255Google Scholar
  42. Dorje F, Friebe T, Tacke R, Mutschler E, Lambrecht G (1990): Novel pharmacological profile of muscarinic receptors mediating contraction of guinea-pig uterus. Naunyn Schmiedebergs Arch Pharmacol 343: 284–289Google Scholar
  43. Dorje F, Levey A, Brann MR (1991a): Immunological detection of muscarinic receptor subtype proteins (ml-m5) in rabbit peripheral tissues. Mol Pharmacol 40: 459–462Google Scholar
  44. Dorje F, Wess J, Lambrecht G, Mutschler E, Brann MR (1991b): Antagonist binding studies at five cloned human muscarinic receptor subtypes. J Pharmacol Exp Ther 256: 727–733Google Scholar
  45. Dousmanis AG, Pennefather PS (1989): Characterization of the inwardly-rectifying conductances in AtT-20 cells. Biophys J 55: 546Google Scholar
  46. Dutar P, Nicoll, RA (1988): Stimulation of phosphatidylinositol (PI) turnover may mediate the muscarinic suppression of the m-current in hippocampal pyramidal cells. Neurosci Lett 85: 89–94Google Scholar
  47. Egan TM, North RA (1986): Acetylcholine hyperpolarizes central Neurons by acting on an M2 muscarinic receptor. Nature 319: 405–407Google Scholar
  48. Ellis J, Huyler J, Brann MR (1991): Allosteric regulation of cloned ml-m5 muscarinic receptor subtypes. Biochem Pharmacol 42: 1927–1932Google Scholar
  49. Ellis J, Seidenberg M (1989): Gallamine exerts biphasic allosteric effects at muscarinic receptors. Mol Pharmacol 35: 173–176Google Scholar
  50. Eltze M, Gmelin G, Wess J, Strohmann C, Tacke R, Mutschler E, Lambrecht G (1988): Muscarinic Ml and M2 receptors mediating opposite effects on neuromuscular transmission in rabbit vas deferens. Eur J Pharmacol 151: 205–221Google Scholar
  51. Feifel R, Wagner-Roder M, Strohmann C, Tacke R, Waelbroeck M, Christophe J, Mutschler E, Lambrecht G (1990): Stereo selective inhibition of muscarinic receptor subtypes by the enantiomers of hexahydrodifenidol and acetylenic analogues. Br J Pharmacol 99: 455–460Google Scholar
  52. Felder CC, Kanterman RY, Ma AL, Axelrod J (1989): A transfected ml muscarinic acetylcholine receptor stimulates adenylate cyclase via phosphatidyl inositol hydrolysis. J Biol Chem 264: 20356–20362Google Scholar
  53. Fischmeister R, Hartzell HC (1986): Mechanism of action of acetylcholine on calcium current in single cells from frog ventricle. J Physiol (Lond) 376: 183–202Google Scholar
  54. Fischmeister R, Hartzell HC (1987): Cyclic guanosine 3′,5′-monophosphate regulates the calcium current in single cells from frog ventricle. J Physiol (Lond) 387: 453–472Google Scholar
  55. Freedman SB, Harley EA, Iversen LL (1988): Biochemical measurement of muscarinic receptor efficacy and its role in receptor regulation. Trends Pharmacol Sci [Suppl] 3: 54–60Google Scholar
  56. Fukuda K, Higashida H, Kubo T, Maeda A, Akiba I, Bujo H, Mishina M, Numa S (1988): Selective coupling with K+ currents of muscarinic acetylcholine receptor subtypes in NG108-15 cells. Nature (Lond) 335: 355–358Google Scholar
  57. Fukuda K, Kubo T, Akiba I, Maeda A, Mishina M, Numa S (1987): Molecular distinction between muscarinic acetylcholine receptor subtypes. Nature 327: 623–625Google Scholar
  58. Gahwiler BH, Brown DA (1987): Muscarine affects calcium currents in rat hippocampal pyramidal cells in vitro. Neurosci Lett 76: 301–306Google Scholar
  59. Galligan J J, North RA, Tokimasa T (1989): Muscarinic agonists and potassium currents in guinea-pig myenteric Neurones. Br J Pharmacol 96: 193–203Google Scholar
  60. Gil DW, Wolfe BB (1985): Pirenzepine distinguishes between muscarinic receptor-mediated phosphoinositide breakdown and inhibition of adenylate cyclase. J Pharmacol Exp Ther 232: 608–616Google Scholar
  61. Gutkind JS, Novotny EA, Brann MR, Robbins K (1991): Muscarinic acetylcholine receptor subtypes as agonist dependent oncogenes. Proc Natl Acad Sci USA 88: 4703–4707Google Scholar
  62. Haga K, Haga T (1983): Affinity chromatography of the muscarinic acetylcholine receptor. J Biol Chem 258: 13575–13579Google Scholar
  63. Hammer R, Berrie CP, Birdsall JM, Burgen ASV, Hulme EC (1980): Pirenzepine distinguishes between different subclasses of muscarinic receptors. Nature 283: 90–92Google Scholar
  64. Harden TK, Tanner LI, Martin MW, Nakahata K, Hugher AR, Kepler JR, Evans T, Masters SB, Brown JH (1986): Characteristics of two biochemical responses to stimulation of muscarinic cholinergic receptors. Trends Pharmacol Sci [Suppl] 7: 14–18Google Scholar
  65. Hartzell HC (1988): Regulation of cardiac ion channels by catecholamines, acetylcholine and second messenger systems. Prog Biophys Mol Biol 52: 165–247Google Scholar
  66. Hartzell HC, Fischmeister R (1987): Effect of forskolin and acetylcholine on calcium current in single isolated cardiac myocytes. Mol Pharmacol 32: 639–645Google Scholar
  67. Henis YI, Kloog Y, Sokolovsky M (1989): Allosteric interactions of muscarinic receptors and their regulation by other membrane proteins. In: The Muscarinic Receptors, Brown JH, ed. Clifton, New Jersey: Humana Press, pp 377–418Google Scholar
  68. Higashida H, Hashii M, Fukuda K, Gaulfield MP, Numa S, Brown DA (1990): Selective coupling of different muscarinic acetylcholine receptors to Neuronal calcium currents in DNA-transfected cells. Proc R Soc Lond [Biol] 242: 68–74Google Scholar
  69. Hille B (1989): Ionic channels: Evolutionary origins and modern roles. Q J Exp Physiol 74: 785–804Google Scholar
  70. Hoss W, Messer WS, Monsma FJ, Miller MD, Ellerbrock BR, Scranton T, Ghodsi-Hovsepian S, Price MA, Balan S, Mazloum Z, Bohnett M (1990): Biochemical and behavioral evidence for muscarinic autoreceptors in the CNS. Brain Res 517: 195–201Google Scholar
  71. Hulme EC, Birdsall NJM, Buckley NJ (1990): Muscarinic receptor subtypes. Annu Rev Pharmacol Toxicol 30: 633–673Google Scholar
  72. Inoue M, Kuriyama H (1991): Muscarinic receptor is coupled with a cation channel through a GTP-binding protein in guinea-pig chromaffin cells. J Physiol (Lond) 436: 511–529Google Scholar
  73. James MK, Cubeddu LX (1987): Pharmacological characterization and functional role of muscarinic autoreceptors in the rabbit striatum. J Pharmacol Exp Ther 240: 203–215Google Scholar
  74. Jones SVP (1991): Effects of muscarinic receptor subtypes on an inward potassium conductance and on exocytosis. Neurosci Soc Abstr 17: 67Google Scholar
  75. Jones SVP, Barker JL, Bonner TI, Buckley NJ, Brann MR (1988a): Electrophysiological characterization of the cloned ml muscarinic receptor expressed in A9 L cells. Proc Natl Acad Sci USA 85: 4056–4060Google Scholar
  76. Jones SVP, Barker JL, Buckley NJ, Bonner TI, Collins R, Brann MR (1988b): Cloned muscarinic receptor subtypes expressed in A9 L cells differ in their coupling to electrical responses. Mol Pharmacol 34: 421–426Google Scholar
  77. Jones SVP, Barker J, Goodman M, Brann MR (1990): IP3 mediates muscarinic receptor-activated calcium-dependent conductances in ml- and m3-transfected A9 cells. J Physiol (Lond) 421: 499–519Google Scholar
  78. Jones SVP, Choi OH, Beaven MA (1991a): Carbachol induces secretion in a mast cell line (RBL-2H3) transfected with the ml muscarinic receptor gene. FEBS Lett 289: 47–50Google Scholar
  79. Jones SVP, Heilman CJ, Brann MR (1991b): Functional responses of cloned muscarinic receptors expressed in CHO-K1 cells. Mol Pharmacol 40: 242–247Google Scholar
  80. Kenakin T (1986): Receptor reserve as a tissue misnomer. Trends Pharmacol Sci 5: 323–346Google Scholar
  81. Kenakin T, Boselli C (1989): Pharmacologic discrimination between receptor heterogeneity and allosteric interaction: Resultant analysis of gallamine and pirenzepine antagonism of muscarinic responses in rat trachea. J Pharmacol Exp Ther 250: 944–952Google Scholar
  82. Kilbinger H, Schworer H, Suss KD (1989): Muscarinic modulation of acetylcholine release: Receptor subtypes and possible mechanisms. Experientia [Suppl] 57: 197–203Google Scholar
  83. King K, Dohlman HG, Thorner J, Caron MG, Lefkowitz RJ (1990): Control of yeast mating signal transduction by a mammalian ß2-adrenergic receptor and Gs a subunit. Science 250: 121–123Google Scholar
  84. Kirsh GE, Yatani A, Codina J, Birnbaumer L, Brown AM (1988): Alpha-subunit of GK activates atrial potassium channels of chick, rat and guinea pig. Am J Physiol 254: 1200–1205Google Scholar
  85. Kleuss C, Hescheler J, Ewel C, Rosenthal W, Schultz G, Wittig B (1991): Assignment of G-protein subtypes to specific receptors inducing inhibition of calcium currents. Nature 353: 43–48Google Scholar
  86. Knopfel T, Vranesic I, Gahwiler BH, Brown DA (1990): Muscarinic and ß-adrenergic depression of the slow calcium-activated potassium conductance in hippocampal CA3 pyramidal cells is not mediated by a reduction of depolarization-induced cytosolic calcium transients. Proc Natl Acad Sci USA 87: 4083–4087Google Scholar
  87. Kubo T, Bujo H, Akiba I, Nakai J, Mishina M, Numa S (1988): Location of a region of the muscarinic acetylcholine receptor involved in selective effector coupling. FEBS Lett 241: 119–125Google Scholar
  88. Kubo T, Fukuda K, Mikami A, Maeda A, Takahashi H, Mishina T, Haga K, Haga A, Ichiyama A, Kangawa K, Kojima M, Matsuo H, Hirose T, Numa S (1986a): Cloning, sequencing and expression of complementary DNA encoding the muscarinic acetylcholine receptor. Nature 323: 411–416Google Scholar
  89. Kubo T, Maeda A, Sugimoto K, Akiba I, Mikami A, Takahasi T, Haga K, Haga A, Ichiyama A, Kanagawa K, Matsuo H, Hirose T, Numa S (1986b): Primary structure of porcine cardiac muscarinic acetylcholine receptor deduced from the cDNA sequence. FEBS Lett 209: 367–372Google Scholar
  90. Kwatra MM, Benovic JL, Caron MG, Lefkowitz RJ, Hosey MM (1989): Phosphorylation of chick heart muscarinic cholinergic receptors by the ß-adrenergic receptor kinase. Biochemistry 28: 4543–4547Google Scholar
  91. Lambrecht G, Feifel R, Moser U, Aasen AJ, Waelbroeck M, Christophe J, Mutschler E (1988): Stereoselectivity of the enantiomers of trihexyphenidyl and its methiodide at muscarinic receptor subtypes. Eur J Pharmacol 155: 167–170Google Scholar
  92. Lazareno S, Buckley NJ, Roberts F (1990): Characterization of muscarinic M4 binding sites in rabbit lung, chicken heart, and NG108-15 cells. Mol Pharmacol 38: 805–815Google Scholar
  93. Lechleiter J, Girard S, Clapman D, Peralta E (1991a): Subcellular patterns of calcium release determined by G protein-specific residues of muscarinic receptors. Nature 350: 505–508Google Scholar
  94. Lechleiter J, Hellmiss R, Duerson K, Ennulat D, David N, Clapham D, Peralta E (1991b): Distinct sequence elements control the specificity of G protein activation by muscarinic acetylcholine receptor subtypes. EMBO J 9: 4381–4390Google Scholar
  95. Levey AI, Simonds W, Spiegel A, Brann MR (1989): Characterization of muscarinic receptor subtype specific antibodies. Soc Neurosci Abstr 15: 64Google Scholar
  96. Levey AI, Stormann TM, Brann MR (1990): Bacterial expression of human muscarinic receptor fusion proteins and generation of subtype-specific antisera. FEBS Lett 275: 65–69Google Scholar
  97. Levey AI, Kitt C, Simonds W, Price D, Brann MR (1991): Identification and localization of muscarinic receptor subtype proteins in rat brain. J Neurosci 11: 3218–3226Google Scholar
  98. Levine RR, Birdsall NJM, (1989): Subtypes of muscarinic receptors IV. Trends Pharmacol Sci [Suppl] 10: 1–119Google Scholar
  99. Liao C-F, Themmen APN, Joho R, Barberis C, Birnbaumer M, Birnbaumer L (1989): Molecular cloning and expression of a fifth muscarinic acetylcholine receptor. J Biol Chem 264: 7328–7337Google Scholar
  100. Luthin GR, Harkness J, Artymyshyn RP, Wolfe BB (1988): Antibodies to a synthetic peptide can be used to distinguish between muscarinic acetylcholine receptor binding sites in brain and heart. Mol Pharmacol 34: 327–333Google Scholar
  101. Madison DV, Lancaster B, Nicoll RA (1987): Voltage clamp analysis of cholinergic action in hippocampus. J Neurosci 7: 733–741Google Scholar
  102. Maeda A, Kubo T, Mishina M, Numa S (1988): Tissue distribution of mRNAs encoding mucarinic acetylcholine receptor subtypes. FEBS Lett 239: 339–342Google Scholar
  103. Malenka RC, Madison DV, Andrade R, Nicoll A (1986): Phorbol esters mimic some cholinergic actions in hippocampal pyramidal Neurons. Neurosci 6: 475–480Google Scholar
  104. Marchi M, Raiteri M (1989): Interaction acetylcholine-glutamate in rat hippocampus: Involvement of two subtypes of M2 muscarinic receptors. J Pharmacol Exp Ther 248: 1255–1260Google Scholar
  105. Marty A (1987): Control of ionic currents and fluid secretion by muscarinic agonists in exocrine glands. Trends Neurosci 10: 373–377Google Scholar
  106. Mash DC, Flynn DD, Potter LT (1985): Loss of M2 muscarine receptors in the cerebral cortex in Alzheimer’s disease and experimental cholinergic denervation. Science 228: 1115–1117Google Scholar
  107. Mash DC, Potter LT (1985): Autoradiographic localization of Ml and M2 muscarine receptors in the rat brain. Neuroscience 19: 551–564Google Scholar
  108. Mayer EM, Otero DH (1985): Pharmacological and ionic characterizations of the muscarinic receptors modulating [3H] acetylcholine release from rat cortical synaptosomes. J Neurosci 5: 1202–1207Google Scholar
  109. McCormick DA, Prince DA (1986): Acetylcholine induces burst firing in thalamic reticular Neurons by activating a potassium conductance. Nature 319: 402–404Google Scholar
  110. McKinney M, Anderson D, Forray C, El-Fakahany EE (1989): Characterization of the striatal M2 muscarinic receptor mediating inhibition of cyclic AMP using selective antagonists: A comparison with the brainstem M2 receptor. J Pharmacol Exp Ther 250: 565–572Google Scholar
  111. Mei L, Roeske WR, Izutsu KT, Yamamura HI (1990): Characterization of muscarinic acetylcholine receptors in human labial salivary glands. Eur J Pharmacol 176: 367–370Google Scholar
  112. Mitchelson F (1988): Muscarinic receptor differentiation. Pharmacol Ther 37: 357–423Google Scholar
  113. Muller W, Misgeld U (1986): Slow cholinergic excitation of guinea pig hippocampal Neurones is mediated by two muscarinic receptor subtypes. Neurosci Lett 67: 107–112Google Scholar
  114. Nakajima Y, Nakajima S, Leonard RJ, Yamaguchi K (1986): Acetylcholine raises excitability by inhibiting the fast transient potassium current in cultured hippocampal Neurons. Proc Natl Acad Sci USA 83: 3022–3026Google Scholar
  115. Nathanson NM (1987): Molecular properties of the muscarinic acetylcholine receptor. Annu Rev Neurosci 10: 195–236Google Scholar
  116. Neher E, Marty KA, Fukuda K, Kubo T, Numa S (1988): Intracellular calcium release mediated by two muscarinic receptor subtypes. FEBS Lett 240: 88–94Google Scholar
  117. Newberry NR, Priestly T (1987): Pharmacological differences between two muscarinic responses of the rat superior cervical ganglion in vitro. Br J Pharmacol 92: 817–826Google Scholar
  118. Nicoll RA (1988): The coupling of neurotransmitter receptors to ion channels in the brain. Science 241: 545–551Google Scholar
  119. North RA (1989): Muscarinic cholinergic regulation of ion channels. In: Muscarinic Receptor Subtypes, Brown JH, ed. Clifton, New Jersey: Humana Press, pp 341–375Google Scholar
  120. North RA, Slack BE, Suprenant A (1985): Muscarinic Ml and M2 receptors mediate depolarization and presynaptic inhibition in guinea-pig enteric nervous system. J Physiol (Lond) 368: 435–453Google Scholar
  121. Novotny E, Brann MR (1989): Agonist pharmacology of cloned muscarinic receptors. Trends Pharmacol Sci [Suppl] 4:Abstr 66Google Scholar
  122. O’Dowd BF, Hnatowich M, Caron MG, Lefkowitz RJ, Bouvier M (1989): Palmi-toylation of the human /32-adrenergic receptor. J Biol Chem 264: 7564–7569Google Scholar
  123. Ovchinnikov YA, Abdulaev NG, Bogachuk AS (1988): Two adjacent cysteine residues in the C-terminal cytoplasmic fragment of bovine rhodopsin are palmitylated. FEBS Lett 230: 1–5Google Scholar
  124. Palacios JM, Bolliger G, Closse A, Enz A, Gmelin G, Malanowski J (1986): The pharmacological assessment of RS 86 (2-ethyl-8-methyl-2,8-diazaspiro-(4,5)- decan-l,3-dion hydrobromide) a potent, specific muscarinic acetylcholine receptor agonist. Eur J Pharmacol 125: 45–62Google Scholar
  125. Palmer JM, Wood JD, Zafirov DH (1987): Purinergic inhibition in the small intestinal myenteric plexus of the guinea-pig. J Physiol (Lond) 387: 357–368Google Scholar
  126. Parker EM, Kameyama K, Higashijima T, Ross M (1991): Reconstitutively active G protein-coupled receptors purified from baculovirus-infected insect cells. J Biol Chem 266: 519–527Google Scholar
  127. Pepeu G (1973): The release of acetylcholine from brain: An approach to the study of the central cholinergic mechanisms. Prog Neurobiol 2: 257–288Google Scholar
  128. Peralta EG, Ashkenazi A, Winslow JW, Ramachandran J, Capon DJ (1988): Differential regulation of PI hydrolysis and adenylyl cyclase by muscarinic receptor subtypes. Nature 334: 434–437Google Scholar
  129. Peralta EG, Ashkenazi A, Winslow JW, Smith DH, Ramachandran J, Capon DJ (1987a): Distinct primary structures, ligand-binding properties and tissue-specific expression of four human muscarinic acetylcholine receptors. EMBO J 6: 3923–3929Google Scholar
  130. Peralta EG, Winslow JW, Peterson GL, Smith DH, Ashkenazi A, Ramachandran J, Schimerlik MI, Capon DJ (1987b): Primary structure and biochemical properties of an M2 muscarinic receptor. Science 236: 600–605Google Scholar
  131. Petersen OH, Gallacher DV (1988): Electrophysiology of pancreatic and salivary acinar cells. Annu Rev Physiol 50: 65–80Google Scholar
  132. Peterson GL, Herron GS, Yamaki M, Fullerton DS, Schimerlik MJ (1984): Purification of the muscarinic acetylcholine receptor from porcine atria. Proc Natl Acad Sci USA 81: 4993–4997Google Scholar
  133. Pfaffinger PJ, Leibowitz MD, Subers EM, Nathanson NM, Aimers W, Hille B (1988): Agonists that suppress M-current elicit phosphoinositide turnover and Ca2+ transients, but these events do not explain M-current suppression. Neuron 1: 477–484Google Scholar
  134. Pfaffinger PJ, Martin JM, Hunter DD, Nathanson NM, Hille B (1985): GTP- binding proteins couple cardiac muscarinic receptors to a potassium channel. Nature 317: 536–538Google Scholar
  135. Pittel Z, Heldman E, Rubinstein R, Cohen S (1990): Distinct muscarinic receptor subtypes differentially modulate acetylcholine release from corticocerebral synaptosomes. JNeurochem 55: 665–672Google Scholar
  136. Poyner DR, Birdsall NJ, Curtis C, Eveleigh P, Hulme EC, Pedder EK, Wheatley M (1989): Binding and hydrodynamic properties of muscarinic receptor subtypes solubilized in 3-(3-cholamidopropyl) dimethylammonio-2-hydroxy-l-propane- sulfonate. Mol Pharmacol 36: 420–429Google Scholar
  137. Quirion R, Aubert I, Lapchak PA, Schaum RP, Teolis S, Gauthier S, Araujo DM (1989): Muscarinic receptor subtypes in human neurodegenerative disorders: Focus on Alzheimer’s disease. Trends Pharmacol Sci [Suppl] 4: 80–84Google Scholar
  138. Raiteri M, Marchi M, Costi A, Volpe G (1990a): Endogenous aspartate release in the rat hippocampus is inhibited by M2 “cardiac” muscarinic receptors. Eur J Pharmacol 177: 181–187Google Scholar
  139. Raiteri M, Marchi M, Paudice P (1990b): Presynaptic muscarinic receptors in the central nervous system. Ann NY Acad Sci 604: 113–129Google Scholar
  140. Raiteri M, Marchi M, Paudice P, Pittaluga A (1990c): Muscarinic receptors mediating inhibition of 7-aminobutyric acid release in rat corpus striatum and their pharmacological characterization. J Pharmacol Exp Ther 254: 496–501Google Scholar
  141. Ringdahl B, Roch M, Jenden DJ (1987): Regional differences in receptor reserve for analogs of oxotremorine in vivo: Implications for development of selective muscarinic agonists. J Pharmacol Exp Ther 242: 464–471Google Scholar
  142. Schultz G, Rosenthal W, Hescheler J (1990): Role of G-proteins in calcium channel modulation. Annu Rev Physiol 52: 275–292Google Scholar
  143. Shapiro RA, Nathanson NM (1989): Deletion analysis of the mouse ml muscarinic acetylcholine receptor: Effects on phosphoinositide metabolism and down-regulation. Biochemistry 28: 8946–8950Google Scholar
  144. Shapiro RA, Wakimoto BT, Subers EM, Nathanson NM (1989): Characterization and functional expression in mammalian cells of genomic and cDNA clones encoding a Drosophila muscarinic acetylcholine receptor. Proc Natl Acad Sci USA 86: 9039–9043Google Scholar
  145. Stein R, Pinkas-Kramarski R, Sokolovsky M (1988): Cloned Ml muscarinic receptors mediate both adenylate cyclase inhibition and phosphoinositide turnover. EMBO J 7: 3031–3035Google Scholar
  146. Stockton JM, Birdsall NJM, Burgen ASV, Hulme EC (1983): Modification of the binding properties of muscarinic receptors by gallamine. Mol Pharmacol 23: 551–557Google Scholar
  147. Sunderland T, Tariot PN, Newhouse PA (1988): Differential responsivity of mood, behavior, and cognition to cholinergic agents in elderly neuropsychiatrie populations. Brain Res Rev 13: 371–389Google Scholar
  148. Szabo G, Otero AS (1990): G-protein mediated regulation of potassium channels in heart. Annu Rev Physiol 52: 293–305Google Scholar
  149. Szerb JC, Somogyi GT (1973): Depression of acetylcholine release from cortical slices by cholinesterase inhibition and oxotremorine. Nature 241: 121–123Google Scholar
  150. Tietje KM, Goldman PS, Nathanson NM (1990): Cloning and functional analysis of a gene encoding a novel muscarinic acetylcholine receptor expressed in chick heart and brain. J Biol Chem 265: 2828–2834Google Scholar
  151. Toselli M, Lang J, Costa T, Lux HD (1989): Direct modulation of voltage- dependent calcium channels by muscarinic activation of a pertussis toxin sensitive G-protein in hippocampal Neurons. Pfluegers Arch 415: 255–261Google Scholar
  152. Toselli M, Lux HD (1989): Opposing effects of acetylcholine on two classes of voltage-dependent calcium channels in hippocampal Neurons. Experientia [Suppl] 57: 97–103Google Scholar
  153. Trautwein W, Hescheler J (1990): Regulation of cardiac L-type calcium current by phosphorylation and G-proteins. Annu Rev Physiol 52: 257–274Google Scholar
  154. Tse A, Clark RB, Giles WR (1990): Muscarinic modulation of calcium current in Neurones from the interatrial septum of bull-frog heart. J Physiol (Lond) 427: 127–149Google Scholar
  155. Van Koppen CJ, Nathanson NM (1990): Site-directed mutagenesis of the m2 muscarinic acetylcholine receptor. J Biol Chem 265: 20887–20892Google Scholar
  156. Van Koppen CJ, Nathanson NM (1991): The cysteine residue in the carboxyl terminal domain of the m2 muscarinic acetylcholine receptor is not required for formation of adenylate cyclase. J NeurochemIn press.Google Scholar
  157. Vivaudou MB, Clapp LH, Walsh JV, Singer JJ (1988): Regulation of one type of calcium current in smooth muscle cells by diacylglycerol and acetylcholine. FASEB J 2: 2497–2504Google Scholar
  158. Waelbroeck M, Tastenoy M, Camus J, Christophe J (1990): Binding of selective antagonists to four muscarinic receptors (M1-M4) in rat forebrain. Mol Pharmacol 38: 267–273Google Scholar
  159. Wanke E, Ferroni A, Malgaroli A, Ambrosini A, Pozzan T, Meldolesi J (1987): Activation of a muscarinic receptor selectively inhibits a rapidly inactivating calcium current in rat sympathetic Neurons. Proc Natl Acad Sci USA 84: 4313–4317Google Scholar
  160. Wanke E, Sardini A, Ferroni A (1989): L and N Ca2+ channels coupled to muscarinic receptors in rat sensory Neurons. Ann NY Acad Sci 560: 398–400Google Scholar
  161. Weiner DM, Brann MR (1989): Distribution of ml-m5 muscarinic acetylcholine receptor mRNAs in rat brain. Trends Pharmacol Sci [Suppl] 4: 115Google Scholar
  162. Weiner DM, Levey A, Brann MR (1990): Expression of muscarinic acetylcholine and dopamine receptor mRNAs within the basal ganglia. Proc Natl Acad Sci USA 87: 7050–7054Google Scholar
  163. Wess J, Bonner TI, Dorje F, Brann MR (1990a): Delineation of muscarinic receptor domains conferring selectivity of coupling to G proteins and second messengers. Mol Pharmacol 38: 517–523Google Scholar
  164. Wess J, Bonner TI, Brann MR (1990b): Chimeric m2/m3 muscarinic receptors: Role of carboxyl terminal receptor domains in selectivity of ligand binding and coupling to phosphoinositide hydrolysis. Mol Pharmacol 38: 872–877Google Scholar
  165. Wess J, Brann MR, Bonner TI (1989): Identification of a small intracellular region of the muscarinic m3 receptor as a determinant of selective coupling to PI turnover. FEBS Lett 258: 133–136Google Scholar
  166. Wess J, Gdula D, Brann MR (1991a): Chimeric m2/m5 muscarinic receptors: Identification of receptor domains confering antagonist binding selectivity. Mol Pharmacol 41: 369–374Google Scholar
  167. Wess J, Gdula D, Brann MR (1991b): 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 10: 3729–3734Google Scholar
  168. Wess J, Lambrecht G, Mutschler E, Brann MR, Dorje F (1991c): Selectivity profile of the novel muscarinic antagonist UH-AH 37 determined by the use of cloned receptors and isolated tissue preparations. Br J Pharmacol 102: 246–250Google Scholar
  169. Whitehouse PJ, Price DL, Struble RG, Clark AW, Coyle JT, DeLong MR (1982): Alzheimer’s disease and senile dementia: loss of Neurons in the basal forebrain. Science 215: 1237–1239Google Scholar
  170. Wolfe BB (1989): Subtypes of muscarinic cholinergic receptors: Ligand binding, functional studies, and cloning. In: The Muscarinic Receptors, Brown JH, ed. Clifton, New Jersey: Humana Press, pp 125–150Google Scholar
  171. Xu M, Yamamoto T, Kato T (1990): In vivo striatal dopamine release by Ml muscarinic receptors is induced by activation of protein kinase C. J Neurochem 54: 1917–1919Google Scholar

Copyright information

© Birkhäuser Boston 1992

Authors and Affiliations

  • S. V. Penelope Jones
  • Allan I. Levey
  • David M. Weiner
  • John Ellis
  • Elizabeth Novotny
  • Shua-Hua Yu
  • Frank Dorje
  • Jurgen Wess
  • Mark R. Brann

There are no affiliations available

Personalised recommendations