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Review ArticleReview

International Union of Pharmacology. XVII. Classification of Muscarinic Acetylcholine Receptors

Malcolm P. Caulfield and Nigel J. M. Birdsall
Pharmacological Reviews June 1998, 50 (2) 279-290;
Malcolm P. Caulfield
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Nigel J. M. Birdsall
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    Figure 1

    Muscarinic antagonists.

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    Figure 2

    pKB(app) values for rabbit vas deferens functional assays versus pKB values on cloned muscarinic receptors. The functional (apparent) pKB values for six selective muscarinic antagonists obtained in Aruklashana-Schild-type experiments on rabbit vas deferens (Eltze, 1988; Sagrada et al., 1994; Grimm et al., 1994a; Waelbroeck et al., 1994) are compared with the log affinity values (pKB) from binding studies on cloned human receptors (Dörje et al., 1991b; Lambrechtet al., 1997). Where data are not available from work on cloned receptors, results are included from work on defined subtypes in nonhuman species (dicyclomine, Lazareno et al., 1990; O-methoxy silahexocyclium, Waelbroeck et al., 1994). Data have been included for those antagonists whose apparent pKB values on the rabbit vas deferens preparation deviate by more than 0.5 log units from the pKB values at either M1 or M4 receptors.

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    Table 1

    Recent reviews on muscarinic receptors

    CoverageAuthors
    Pharmacology, structure, coupling, localization Hulme et al.(1990)
    Pharmacology, structure, coupling, localization Caulfield (1993)
    Pharmacology, classification techniques Caulfield (1997)
    Muscarinic receptors in smooth muscle Eglen et al.(1996)
    Roles for M2 and M3 receptors in smooth muscle Eglen et al. (1994)
    Species differences Hall et al. (1993)
    Mutational analysis of ligand binding and G-protein-binding residues Wess et al.(1995); Wess (1996)
    Muscarinic receptor toxins Jerusalinsky and Harvey (1994)
    Signal transduction Felder (1995)
    Ion channel coupling Brown et al. (1995)
    Presynaptic muscarinic receptors Grimm et al. (1994b)
    Fuder and Muscholl (1995)
    Newer agonists and antagonists Eglen and Watson (1996)
    Grimm et al. (1994b)
    Muscarinic receptor subtypes symposium Levine and Birdsall (1997)
    • View popup
    Table 2

    Muscarinic receptor genes

    SpeciesSwissProt accession code Number of amino acids (% identity with human sequence)
    M1M2M3M4M5
    Human P11229 P08172 P20309 P08713 P08912
    460466590479532
    Pig P04761 P06199 P11483
    460 (99%)466 (97%)590 (96%)
    Cow P41984
    590 (95%)
    Rat P08482 P10980 P08483 P08485 P08911
    458 (99%)466 (95%)589 (92%)478 (95%)531 (89%)
    Mouse P12657 P30544
    460 (98%)479 (95%)
    Xenopus 2-a P30544
    484 (78%)
    Chicken2-a P30372 P49578 P17200
    466 (92%)2-b 639 (87%)490 (76%)
    • ↵2-a The nonmammalian Xenopus and chicken receptors have been included for comparison. A Drosophilamuscarinic receptor (P13695, 722aa) also has been cloned (Shapiroet al., 1989; Onai et al., 1989), but its sequence does not fit into the current classification.

    • ↵2-b Unusual pharmacology, with approximately ten times higher pirenzepine affinity than mammalian M2 receptors (Tietje and Nathanson, 1991).

    • From Hulme et al. (1990); Hall et al. (1993);Herrera et al. (1994); Eglen et al. (1996), and the SwissProt database.

    • View popup
    Table 3

    Antagonist affinity constants (log affinity constants or pKBvalues) for mammalian muscarinic receptors3-a

    AntagonistReceptor subtype
    M1M2M3M4M5
    Atropine9.0–9.79.0–9.38.9–9.89.1–9.68.9–9.7
    Pirenzepine7.8–8.56.3–6.76.7–7.17.1–8.16.2–7.1
    Methoctramine7.1–7.87.8–8.36.3–6.97.4–8.16.9–7.2
    4-DAMP8.6–9.27.8–8.48.9–9.38.4–9.48.9–9.0
    Himbacine7.0–7.28.0–8.36.9–7.48.0–8.86.1–6.3
    AF-DX 3847.3–7.58.2–9.07.2–7.88.0–8.76.3
    Tripitramine8.4–8.89.4–9.67.1–7.47.8–8.27.3–7.5
    Darifenacin7.5–7.87.0–7.48.4–8.97.7–8.08.0–8.1
    Guanylpirenzepine7.75.56.56.56.8
    PD 1028075.35.76.27.35.2
    MT33-b 7.1<6<68.7<6
    MT73-b 9.8<6<6<6<6
    • ↵3-a Data are from a variety of mammalian species, including human: Hulme et al., 1990; Caulfield, 1993; Maggioet al., 1994; Eglen et al., 1996; Nunn et al., 1996; Adem and Karlsson, 1997; Caulfield, 1997; Levine and Birdsall, 1997; Jolkkonen et al., 1994.

    • ↵3-b Toxins from Eastern Green Mamba venom.

    • View popup
    Table 4

    Muscarinic receptors: G-protein coupling, transduction pathways, localization, and functional responses

    Receptor subtype
    M1M2M3M4M5
    Preferred G-proteinq/11i/oq/11i/oq/11
    Second messengers4-a PLC IP3/DAGAC (−)PLC IP3/DAGAC (−)PLC IP3/DAG
    Ca2+/PKCCa2+/PKCCa2+/PKC
    LocationsBrain (cortex, hippocampus)HeartSmooth muscleBasal forebrainSubstantia
    GlandsHindbrainGlandsStriatum nigra
    Sympathetic gangliaSmooth muscleBrain
    Functional responses4-b M-current inhibitionK+channelsSmooth muscle contractionInhibit Ca2+ channels
    (βγ activates)Gland secretion
    Inhibit Ca2+ channelsDecrease neurotransmitter
    Decrease heart rate and forcerelease (presynaptic)
    Decrease neurotransmitter release (presynaptic)
    • ↵4-a DAG, diacylglycerol; IP3, inositol 1,4,5-trisphosphate; PKC, protein kinase C; PLC, phospholipase C.

    • ↵4-b Main responses; several other responses have been suggested to be elicited by defined subtypes.

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1 Jun 1998
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Review ArticleReview

International Union of Pharmacology. XVII. Classification of Muscarinic Acetylcholine Receptors

Malcolm P. Caulfield and Nigel J. M. Birdsall
Pharmacological Reviews June 1, 1998, 50 (2) 279-290;

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Review ArticleReview

International Union of Pharmacology. XVII. Classification of Muscarinic Acetylcholine Receptors

Malcolm P. Caulfield and Nigel J. M. Birdsall
Pharmacological Reviews June 1, 1998, 50 (2) 279-290;
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  • Article
    • I. Introduction
    • II. Nomenclature
    • III. Molecular Definition of Subtypes
    • IV. Pharmacological Definition of Subtypes
    • V. Transduction Mechanisms and Functional Responses
    • VI. Conclusions
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