Ivermectin: A Positive Allosteric Effector of the α7 Neuronal Nicotinic Acetylcholine Receptor

Abstract

We report that preapplication of ivermectin, in the micromolar range, strongly enhances the subsequent acetylcholine-evoked current of the neuronal chick or human alpha7 nicotinic acetylcholine receptors reconstituted in Xenopus laevis oocytes and K-28 cells. This potentiation does not result from nonspecific Cl- currents. The concomitant increase in apparent affinity and cooperativity of the dose-response curve suggest that ivermectin acts as a positive allosteric effector. This interpretation is supported by the observation of an increase in efficiency of a partial agonist associated with the potentiation and by the differential effect of ivermectin on mutants within the M2 channel domain. Ivermectin effects reveal a novel allosteric site for pharmacological agents on neuronal alpha7 nicotinic acetylcholine receptors.

Comparative pharmacology and computational modelling yield insights into allosteric modulation of human α7 nicotinic acetylcholine receptors

“…In accordance with previous reports, the type II modulator, PNU-120596 greatly enhanced the duration of the response, while the type I modulators investigated exerted a variable effect upon the time course of the responses, but much less markedly so than type II modulators. The similarity of our findings with type I and type II allosteric modulators and those previously reported [11,14,17] also suggests that RIC-3, which …”

“…3). These findings resemble and extend those obtained previously in the absence of RIC-3 [11,14,17]. The type I modulators, IVM (30 M), 5-hydroxyindole (1mM), NS-1738 (10M) and genistein (10M), enhanced 7 responses to 123 ± 7 % (n=5), 300 ± 91%, (n=3), 1740 ± 1358 % (n=3) and 376 ± 77%, (n=3) respectively, while the type II modulator, PNU-120596 (3M) enhanced 7 responses by 1867 ± 871 % (n=4).…”

“…For example, the hitherto elusive steroid site on the GABA receptor was identified in a comprehensive comparison between Drosophila melanogaster GABA-gated chloride channels and human GABA A type receptors [16]. We have previously shown that the anthelmintic compound, IVM, enhanced ACh-induced 7 amplitude responses, confirming the earlier finding of Bertrand and colleagues [17], while slightly attenuating responses of ACR-16 [18] , a Caenorhabditis elegans α7 homologue [19,20]. ACR-16 and 7 nAChR subunits share considerable amino acid sequence identity of 47% but show important differences in residues considered important in allosteric drug actions (Fig.…”

Ryanodine is a Positive Modulator of Acetylcholine Receptor Gating in Cochlear Hair Cells

“…The fact that potentiation occurred within seconds and was reversible suggests that incorporation of receptors, whether newly synthesized or drawn from intracellular stores, seems an unlikely explanation. As has been proposed for the potentiating effect of certain compounds on other nAChRs (Conroy et al 2003;Curtis et al 2002;Hurst et al 2005;Krause et al 1998;Zwart et al 2002), the most likely interpretation of the present results is that ryanodine acts as a positive allosteric effector, recognizing a specific binding site within the receptor protein. Another formal possibility is that ryanodine is having its effect through Fconformational coupling_ between hair cell AChRs and ryanodine receptors (RyR) as occurs during calcium release from sarcoplasmic reticulum in skeletal muscle.…”

Modulation of spontaneous hippocampal synaptic events with 5-hydroxyindole, 4OH-GTS-21, and rAAV-mediated α7 nicotinic receptor gene transfer

“…Known positive modulators of α7 nAChR include ivermectin (Krause et al, 1998), galantamine (Santos et al, 2002), PNU-120596 (Hurst et al, 2005), TQS (4,5,9b-tetrahydro-3-H-cyclopenta [c] quinoline-8-sulfonic acid amide) (Gronlien et al, 2007), and 5-hydroxyindole (5-HI) (Gurley et al, 2000;Zwart et al, 2002). However, 5-HI also produces a number of other physiological effects.…”