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 a4b2 neuronal nicotinic receptor activity. We explored its effect on the human a7 neuronal nicotinic acetylcholine receptor (nAChR) expressed in Xenopus oocytes. 2 Galantamine, at a concentration of 0.1 mM, increased the amplitude of acetylcholine (ACh)-induced ion currents in the human a7 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 mM 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 mM. 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 mM ACh. 4 Galantamine affects not only the activity of post-synaptic receptors but also the activity of nerve terminals. At a concentration of 1 mM, 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 mM. 5 In conclusion, our results show that galantamine enhances human a7 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.

Ecto-nucleoside triphosphate diphosphohydrolases (E-NTPDases) are widely expressed enzymes implicated in the modulation of nucleotide cell signaling. They dephosphorylate either ATP or ADP in the presence of divalent cations, and efforts have been made to identify efficient inhibitors. E-NTPDase activity has been described in Torpedo electric organ electrocytes. We show here that gadolinium, an established blocker of stretch-activated channels, efficiently inhibits E-NTPDase activity of Torpedo electric organ (Ki = 3 microM for ATPase) as well as apyrase from potato tuber, frequently used in inhibition experiments. To our knowledge, gadolinium is the most potent inhibitor described to date for both membrane-bound and soluble E-NTPDases.

Ros, Esteve, Jordi Aleu, Inmaculada Gomez de Aranda, Carles Cantí, Yuan-Ping Pang, Jordi Marsal, and Carles Solsona. Effects of bis (7)-tacrine on spontaneous synaptic activity and on the nicotinic ACh receptor of Torpedo electric organ. J Neurophysiol 86: [183][184][185][186][187][188][189] 2001. 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 M) in Torpedo electric organ membranes transplanted in Xenopus laevis oocytes. Bis(7)-tacrine inhibited the acetylcholine-induced currents in a reversible manner (IC 50 ϭ 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 Ϫ0.72 Ϯ 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 ␣-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.