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Exploring the Positive Allosteric Modulation of Human α7 Nicotinic Receptors from a Single-Channel Perspective

Andersen, ND and Nielsen, BE and Corradi, J and Tolosa, MF and Feuerbach, Dominik and Arias, HR and Bouzat, C (2016) Exploring the Positive Allosteric Modulation of Human α7 Nicotinic Receptors from a Single-Channel Perspective. Neuropharmacology.

Abstract

Enhancement of 7 nicotinic receptor (nAChR) function by positive allosteric modulators (PAMs) is a promising therapeutic strategy to improve cognitive deficits. PAMs have been classified only on the basis of their macroscopic effects as type I, which only enhance agonist-induced currents, and type II, which also decrease desensitization and reactivate desensitized nAChRs. To decipher the molecular basis underlying these distinct activities, we explored the effects on single-7 channel currents of representative members of each type and of novel compounds, which macroscopically behave as type II PAMs. Our results reveal that both types of PAMs enhance open-channel lifetime and produce episodes of successive openings, thus discarding the statement that only type II PAMs affect kinetics. Both PAM types act through different allosteric sites and show different sensitivity to temperature, suggesting different mechanisms of potentiation. Overall, our study provides novel information of 7 potentiation, essential for the still ongoing development of therapeutic compounds.

Item Type: Article
Date Deposited: 26 Apr 2016 23:45
Last Modified: 26 Apr 2016 23:45
URI: https://oak.novartis.com/id/eprint/27615

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