title: Galantamine activates muscle-type nicotinic acetylcholine receptors without binding to the acetylcholine-binding site.
abstract: Galantamine (Reminyl; Janssen Pharmaceutica, Titusville, NJ) belongs to a class of acetylcholinesterase inhibitors approved for symptomatic treatment of Alzheimer's disease. The drug presumably acts by raising and prolonging the profile of acetylcholine (ACh) via an inhibitory effect on the esterase. However, there is also evidence demonstrating that galantamine can activate the nicotinic ACh receptor or modulate its activation by ACh. In this study, we have examined the ability of galantamine to directly activate the muscle-type nicotinic ACh receptor or to modulate receptor activation by selected nicotinic agonists. Studies of direct activation by galantamine demonstrated that this ligand is a low-efficacy agonist of the muscle-type ACh receptor. Point mutations in the M2-M3 linker (alphaS269I) and the M2 transmembrane domain (epsilonT264P) had similar effects on receptor activation by galantamine and nicotinic agonists, suggesting that the general features of receptor activation by galantamine are similar to that in the presence of ACh. Experiments performed in the simultaneous presence of galantamine and various nicotinic ligands showed that channel activation by the nicotinic ligands studied (ACh, carbachol, and choline) was not affected by the presence of galantamine at concentrations up to 100 microm. In addition, galantamine did not reduce the initial rate of binding for 125I-alpha-bungarotoxin. These results demonstrate that galantamine does not interfere with the occupation of the nicotinic agonist binding site by ACh, carbachol, or choline. We conclude that galantamine activates the muscle-type ACh receptor by interacting with a binding site that is distinct from the site for nicotinic agonists.
authors.affiliation: Department of Anesthesiology, Washington University, St. Louis, Missouri 63110, USA. akk@morpheus.wustl.edu
authors.forename: Gustav
authors.initials: G
authors.lastname: Akk
authors.forename: Joe Henry
authors.initials: JH
authors.lastname: Steinbach
mesh_terms: D000109:Acetylcholine / Q000378:metabolism / Q000494:pharmacology; D000200:Action Potentials; D000494:Allosteric Regulation; D019943:Amino Acid Substitution; D000818:Animals; D001665:Binding Sites; D002038:Bungarotoxins / Q000494:pharmacology; D002217:Carbachol / Q000494:pharmacology; D002460:Cell Line; D002794:Choline / Q000494:pharmacology; D002800:Cholinesterase Inhibitors / Q000494:pharmacology*; D005326:Fetal Proteins / Q000737:chemistry / Q000187:drug effects / Q000235:genetics; D005702:Galantamine / Q000494:pharmacology*; D006801:Humans; D015640:Ion Channel Gating / Q000187:drug effects; D007668:Kidney; D008024:Ligands; D051379:Mice; D009124:Muscle Proteins / Q000737:chemistry / Q000187:drug effects* / Q000235:genetics; D020125:Mutation, Missense; D018722:Nicotinic Agonists / Q000494:pharmacology*; D018408:Patch-Clamp Techniques; D017354:Point Mutation; D017434:Protein Structure, Tertiary; D021122:Protein Subunits; D011978:Receptors, Nicotinic / Q000737:chemistry / Q000187:drug effects* / Q000235:genetics; D011993:Recombinant Fusion Proteins / Q000187:drug effects
chemical_list: D002038:Bungarotoxins; D002800:Cholinesterase Inhibitors; D005326:Fetal Proteins; D008024:Ligands; D009124:Muscle Proteins; D018722:Nicotinic Agonists; D021122:Protein Subunits; D011978:Receptors, Nicotinic; D011993:Recombinant Fusion Proteins; D005702:Galantamine; D002217:Carbachol; D002794:Choline; D000109:Acetylcholine
references.citation: J Physiol. 1999 Apr 15;516 ( Pt 2):315-30
references.pmid: 10087333
references.citation: J Physiol. 1976 Sep;260(3):531-52
references.pmid: 10432
references.citation: Proc Natl Acad Sci U S A. 1999 Aug 31;96(18):10466-71
references.pmid: 10468632
references.citation: Br J Pharmacol. 1999 Dec;128(7):1467-76
references.pmid: 10602325
references.citation: Eur J Pharmacol. 2000 Mar 30;393(1-3):165-70
references.pmid: 10771010
references.citation: J Gen Physiol. 2000 Sep;116(3):327-40
references.pmid: 10962011
references.citation: J Physiol. 2000 Sep 15;527 Pt 3:405-17
references.pmid: 10990529
references.citation: J Neurochem. 2000 Dec;75(6):2492-500
references.pmid: 11080202
references.citation: Nature. 2001 May 17;411(6835):269-76
references.pmid: 11357122
references.citation: J Gen Physiol. 2002 Sep;120(3):369-93
references.pmid: 12198092
references.citation: J Physiol. 2002 Nov 1;544(3):695-705
references.pmid: 12411516
references.citation: J Neurobiol. 2002 Dec;53(4):479-500
references.pmid: 12436414
references.citation: J Pharmacol Exp Ther. 2003 Jun;305(3):1024-36
references.pmid: 12649296
references.citation: J Physiol. 2003 Aug 15;551(Pt 1):155-68
references.pmid: 12824448
references.citation: Mol Pharmacol. 2003 Nov;64(5):1217-26
references.pmid: 14573772
references.citation: Eur J Biochem. 1991 Sep 15;200(3):671-7
references.pmid: 1717267
references.citation: Mol Pharmacol. 1991 Jan;39(1):9-12
references.pmid: 1987453
references.citation: Proc R Soc Lond B Biol Sci. 1977 Nov 14;199(1135):231-62
references.pmid: 22856
references.citation: Proc R Soc Lond B Biol Sci. 1985 Sep 23;225(1240):329-55
references.pmid: 2414779
references.citation: Mol Pharmacol. 1985 Dec;28(6):527-38
references.pmid: 2417099
references.citation: J Physiol. 1985 Dec;369:501-57
references.pmid: 2419552
references.citation: J Biol Chem. 1979 May 10;254(9):3315-25
references.pmid: 429353
references.citation: J Physiol. 1972 May;223(1):151-71
references.pmid: 4537943
references.citation: J Gen Physiol. 1973 Jun;61(6):687-708
references.pmid: 4541078
references.citation: Pflugers Arch. 1981 Aug;391(2):85-100
references.pmid: 6270629
references.citation: Mol Pharmacol. 1993 Nov;44(5):1051-5
references.pmid: 7504167
references.citation: Nature. 1993 Dec 9;366(6455):565-9
references.pmid: 7504783
references.citation: Proc Natl Acad Sci U S A. 1995 Jan 31;92(3):758-62
references.pmid: 7531341
references.citation: Eur J Pharmacol. 1995 Aug 15;290(3):207-19
references.pmid: 7589215
references.citation: J Biol Chem. 1994 Apr 8;269(14):10407-16
references.pmid: 8144624
references.citation: J Neurosci. 1994 Jun;14(6):3922-33
references.pmid: 8207496
references.citation: Eur J Biochem. 1993 Sep 1;216(2):671-7
references.pmid: 8375401
references.citation: J Recept Res. 1993;13(1-4):413-36
references.pmid: 8450498
references.citation: J Pharmacol Exp Ther. 1993 Jun;265(3):1474-91
references.pmid: 8510023
references.citation: Biophys J. 1996 Jan;70(1):264-80
references.pmid: 8770203
references.citation: J Physiol. 1996 Jul 1;494 ( Pt 1):155-70
references.pmid: 8814613
references.citation: Eur J Pharmacol. 1996 Aug 15;309(3):287-98
references.pmid: 8874153
references.citation: J Neurosci. 1997 Jan 15;17(2):625-34
references.pmid: 8987785
references.citation: Proc Biol Sci. 1997 Mar 22;264(1380):375-83
references.pmid: 9107053
references.citation: Biophys J. 1998 Jul;75(1):218-25
references.pmid: 9649381
references.citation: J Gen Physiol. 1998 Aug;112(2):181-97
references.pmid: 9689026
references.citation: Biochemistry. 1999 Jan 5;38(1):134-41
references.pmid: 9890891