The Allosteric Potentiation of Nicotinic Acetylcholine Receptors by Galantamine Is Transduced into Cellular Responses in Neurons: Ca²⁺Signals and Neurotransmitter Release.

Abstract

Neuronal nicotinic acetylcholine receptors (nAChR) modulate a variety of cellular responses, including Ca 2ϩ signals and neurotransmitter release, which can influence neuronal processes such as synaptic efficacy and neuroprotection. In addition to receptor activation through the agonist binding site, an allosteric modulation of nAChR has also been described for a novel class of allosteric ligands. Of these, the acetylcholinesterase inhibitor and Alzheimer drug galantamine represents the prototypical allosteric ligand, based on its potentiation of nAChRevoked single-channel and whole-cell currents. The aim of this study was to establish whether the allosteric potentiation of nAChR currents is transduced in downstream cellular responses to nAChR activation, namely increases in intracellular Ca 2ϩ and [ 3 H]noradrenaline release. In SH-SY5Y cells, galantamine potentiated nicotine-evoked increases in intracellular Ca 2ϩ and [ 3 H]noradrenaline release with a bell-shaped concentration-response profile; maximum enhancement of nicotineevoked responses occurred at 1 M galantamine. This potentiation was blocked by mecamylamine, whereas galantamine had no effect on these measures in the absence of nicotine. Galantamine did not compete for radioligand binding to the agonist binding sites of several nAChR subtypes, consistent with an allosteric mode of action. Unlike galantamine, the acetylcholinesterase inhibitors rivastigmine and donepezil did not potentiate nAChR-mediated responses, whereas donepezil was a reasonably potent inhibitor of nicotine-and KCl-evoked increases in Ca 2ϩ . nAChR-mediated [ 3 H]noradrenaline release from hippocampal slices was also potentiated by galantamine, with an additional component attributable to acetylcholinesterase inhibition and subsequent increase in acetylcholine. These results indicate that the allosteric regulation of nAChR results in the potentiation of receptor-dependent cellular processes relevant to many of the physiological consequences of nAChR activation.

Cholinergic drugs potentiate human nicotinic α4β2 acetylcholine receptors by a competitive mechanism

“…Galanthamine also failed to displace [ 3 H]nicotine and [ 3 H]MLA from rat brain a4h2 and a7 nicotinic acetylcholine receptors, respectively, and [ 3 H]epibatidine from human a3* nicotinic acetylcholine receptors in SHSY-5Y cells. The saturation binding curves of these radioligands were also unaffected in the presence of 1 AM galanthamine (Dajas-Bailador et al, 2003). Despite the non-competitive binding, the inhibitory effects exerted by rivastigmine and galanthamine (Fig.…”

Preclinical Investigation of the Functional Effects of Memantine and Memantine Combined with Galantamine or Donepezil

“…Activation of muscle-type nAChRs by galantamine and nicotinic agonists indicated that galantamine interacted with a binding site that was distinct from the site for nicotinic agonists (Akk and Steinbach, 2005). Allosteric potentiation of nAChR currents by galantamine was transduced in downstream cellular responses to nAChR activation, including increases in intracellular Ca 2 + and [ 3 H]noradrenaline release (Dajas-Bailador et al, 2003).…”

“…Galantamine, a mild cholinesterase inhibitor, allosterically modulates nAChRs, including a7 nAChRs. Donepezil, a cholinesterase inhibitor with four to eight times the potency of galantamine, has no demonstrated allosteric effect on a7 nAChRs (eg Dajas-Bailador et al, 2003). Memantine, an NMDA antagonist also blocks a7 nAChRs (eg Aracava et al, 2005;Maskell et al, 2003).…”

Cholinergic deficiency involved in vascular dementia: possible mechanism and strategy of treatment

“…These protective effects were mediated partly by nAChRs. As a potential nicotinic allosteric ligand, galantamine facilitates synaptic transmission in the mammalian central nervous system, which could be an important determinant of its therapeutic effect [120][121][122] . Indeed, galantamine was able to reverse the learning impairment induced by mecamylamine [122] , and the activation of nicotinic receptors makes anti-inflammation of galantamine possible.…”