Effect of galantamine on the human alpha7 neuronal nicotinic acetylcholine receptor, the Torpedo nicotinic acetylcholine receptor and spontaneous cholinergic synaptic activity.
1. Various types of anticholinesterasic agents have been used to improve the daily activities of Alzheimer's disease patients. It was recently demonstrated that Galantamine, described as a molecule with anticholinesterasic properties, is also an allosteric enhancer of human alpha4beta2 neuronal nicotinic receptor activity. We explored its effect on the human alpha7 neuronal nicotinic acetylcholine receptor (nAChR) expressed in Xenopus oocytes. 2. Galantamine, at a concentration of 0.1 microM, increased the amplitude of acetylcholine (ACh)-induced ion currents in the human alpha7 nAChR expressed in Xenopus oocytes, but caused inhibition at higher concentrations. The maximum effect of galantamine, an increase of 22% in the amplitude of ACh-induced currents, was observed at a concentration of 250 microM Ach. 3. The same enhancing effect was obtained in oocytes transplanted with Torpedo nicotinic acetylcholine receptor (AChR) isolated from the electric organ, but in this case the optimal concentration of galantamine was 1 microM. In this case, the maximum effect of galantamine, an increase of 35% in the amplitude of ACh-induced currents, occurred at a concentration of 50 microM ACh. 4. Galantamine affects not only the activity of post-synaptic receptors but also the activity of nerve terminals. At a concentration of 1 microM, quantal spontaneous events, recorded in a cholinergic synapse, increased their amplitude, an effect which was independent of the anticholinesterasic activity associated with this compound. The anticholinesterasic effect was recorded in preparations treated with a galantamine concentration of 10 microM. 5. In conclusion, our results show that galantamine enhances human alpha7 neuronal nicotinic ACh receptor activity. It also enhances muscular AChRs and the size of spontaneous cholinergic synaptic events. However, only a very narrow range of galantamine concentrations can be used for enhancing effects.
Texidó
Laura
L
Laboratory of Molecular and Cellular Neurobiology, Department of Cell Biology and Pathology, Medical School-Bellvitge Campus, IDIBELL-Universitat de Barcelona, Feixa Llarga s/n, L'Hospitalet de Llobregat, E-08907, Spain.
Ros
Esteve
E
Martín-Satué
Mireia
M
López
Susana
S
Aleu
Jordi
J
Marsal
Jordi
J
Solsona
Carles
C
D000818:Animals; D002800:Cholinesterase Inhibitors / Q000494:pharmacology*; D005260:Female; D005702:Galantamine / Q000494:pharmacology*; D006801:Humans; D066298:In Vitro Techniques; D008564:Membrane Potentials / Q000187:drug effects; D018697:Nootropic Agents / Q000494:pharmacology*; D009865:Oocytes / Q000187:drug effects; D010275:Parasympathetic Nervous System / Q000187:drug effects*; D018408:Patch-Clamp Techniques; D011978:Receptors, Nicotinic / Q000187:drug effects*; D013569:Synapses / Q000187:drug effects*; D009435:Synaptic Transmission / Q000187:drug effects; D014101:Torpedo; D014982:Xenopus laevis; D064569:alpha7 Nicotinic Acetylcholine Receptor
D002800:Cholinesterase Inhibitors; C579167:Chrna7 protein, human; D018697:Nootropic Agents; D011978:Receptors, Nicotinic; D064569:alpha7 Nicotinic Acetylcholine Receptor; D005702:Galantamine