Effects of bis(7)-tacrine on spontaneous synaptic activity and on the nicotinic ACh receptor of Torpedo electric organ.
Bis(7)-tacrine is a potent acetylcholinesterase inhibitor in which two tacrine molecules are linked by a heptylene chain. We tested the effects of bis(7)-tacrine on the spontaneous synaptic activity. Miniature endplate potentials (MEPPs) were recorded extracellularly on slices of electric organ of Torpedo marmorata. Bis(7)-tacrine, at a concentration of 100 nM, increased the magnitudes that describe MEPPs: amplitude, area, rise time, rate of rise, and half-width. We also tested the effect of bis(7)-tacrine on nicotinic acetylcholine receptors by analyzing the currents elicited by acetylcholine (100 microM) in Torpedo electric organ membranes transplanted in Xenopus laevis oocytes. Bis(7)-tacrine inhibited the acetylcholine-induced currents in a reversible manner (IC(50) = 162 nM). The inhibition of nicotinic acetylcholine receptors was not voltage dependent, and bis(7)-tacrine increased the desensitization of nicotinic acetylcholine receptors. The Hill coefficient for bis(7)-tacrine was -0.72 +/- 0.02, indicating that bis(7)-tacrine binds to the nicotinic acetylcholine receptor in a molecular ratio of 1:1, but does not affect the binding of alpha-bungarotoxin with the nicotinic acetylcholine receptor. In conclusion, bis(7)-tacrine greatly increases the spontaneous quantal release from peripheral cholinergic terminals at a much lower concentration than tacrine. Bis(7)-tacrine also blocks acetylcholine-induced currents of Torpedo electric organ, although the mechanism is different from that of tacrine: bis(7)-tacrine enhances desensitization, whereas tacrine reduces it.
Ros
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Laboratori de Neurobiologia Cellular i Molecular, Departament de Biologia Cellular i Anatomia Patològica, Facultat de Medicina, Hospital de Bellvitge, Universitat de Barcelona, E-08907 L'Hospitalet de Llobregat, Spain.
Aleu
J
J
Gomez de Aranda
I
I
Cantí
C
C
Pang
Y P
YP
Marsal
J
J
Solsona
C
C
D000818:Animals; D002038:Bungarotoxins / Q000378:metabolism / Q000494:pharmacology; D002800:Cholinesterase Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004557:Electric Organ / Q000187:drug effects / Q000502:physiology*; D005260:Female; D007457:Iodine Radioisotopes; D008564:Membrane Potentials / Q000187:drug effects / Q000502:physiology; D008565:Membrane Proteins / Q000378:metabolism; D009865:Oocytes / Q000502:physiology / Q000637:transplantation; D011978:Receptors, Nicotinic / Q000187:drug effects* / Q000378:metabolism; D012995:Solubility; D009435:Synaptic Transmission / Q000187:drug effects*; D013619:Tacrine / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology*; D014101:Torpedo; D014982:Xenopus laevis
C122128:1,7-N-heptylene-bis-9,9'-amino-1,2,3,4-tetrahydroacridine; D002038:Bungarotoxins; D002800:Cholinesterase Inhibitors; D007457:Iodine Radioisotopes; D008565:Membrane Proteins; D011978:Receptors, Nicotinic; D013619:Tacrine