Article Figures & Data
Figures
- Figure 1
Muscarinic antagonists.
- 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.
Tables
Coverage Authors 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) Species SwissProt accession code Number of amino acids (% identity with human sequence) M1 M2 M3 M4 M5 Human P11229 P08172 P20309 P08713 P08912 460 466 590 479 532 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.
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↵2-b Unusual pharmacology, with approximately ten times higher pirenzepine affinity than mammalian M2 receptors (Tietje and Nathanson, 1991).
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From Hulme et al. (1990); Hall et al. (1993);Herrera et al. (1994); Eglen et al. (1996), and the SwissProt database.
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- Table 3
Antagonist affinity constants (log affinity constants or pKBvalues) for mammalian muscarinic receptors3-a
Antagonist Receptor subtype M1 M2 M3 M4 M5 Atropine 9.0–9.7 9.0–9.3 8.9–9.8 9.1–9.6 8.9–9.7 Pirenzepine 7.8–8.5 6.3–6.7 6.7–7.1 7.1–8.1 6.2–7.1 Methoctramine 7.1–7.8 7.8–8.3 6.3–6.9 7.4–8.1 6.9–7.2 4-DAMP 8.6–9.2 7.8–8.4 8.9–9.3 8.4–9.4 8.9–9.0 Himbacine 7.0–7.2 8.0–8.3 6.9–7.4 8.0–8.8 6.1–6.3 AF-DX 384 7.3–7.5 8.2–9.0 7.2–7.8 8.0–8.7 6.3 Tripitramine 8.4–8.8 9.4–9.6 7.1–7.4 7.8–8.2 7.3–7.5 Darifenacin 7.5–7.8 7.0–7.4 8.4–8.9 7.7–8.0 8.0–8.1 Guanylpirenzepine 7.7 5.5 6.5 6.5 6.8 PD 102807 5.3 5.7 6.2 7.3 5.2 MT33-b 7.1 <6 <6 8.7 <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.
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↵3-b Toxins from Eastern Green Mamba venom.
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- Table 4
Muscarinic receptors: G-protein coupling, transduction pathways, localization, and functional responses
Receptor subtype M1 M2 M3 M4 M5 Preferred G-protein q/11 i/o q/11 i/o q/11 Second messengers4-a PLC IP3/DAG AC (−) PLC IP3/DAG AC (−) PLC IP3/DAG Ca2+/PKC Ca2+/PKC Ca2+/PKC Locations Brain (cortex, hippocampus) Heart Smooth muscle Basal forebrain Substantia Glands Hindbrain Glands Striatum nigra Sympathetic ganglia Smooth muscle Brain Functional responses4-b M-current inhibition K+channels Smooth muscle contraction Inhibit Ca2+ channels (βγ activates) Gland secretion Inhibit Ca2+ channels Decrease neurotransmitter Decrease heart rate and force release (presynaptic) Decrease neurotransmitter release (presynaptic)
