Voltage- and Temperature-Dependent Allosteric Modulation of α7 Nicotinic Receptors by PNU120596
Frontiers in Pharmacology
Copyright: © 2011 Sitzia, Brown, Randall and Dunlop. This is an open-access article distributed under the terms of the Creative Commons Attribution Non Commercial License (https://creativecommons.org/licenses/by-nc/3.0/), which permits non-commercial use, distribution, and reproduction in other forums, provided the original authors and source are credited.
Alpha7 nicotinic acetylcholine receptors (α7 nAChR) are widely distributed throughout the central nervous system and are found at particularly high levels in the hippocampus and cortex. Several lines of evidence indicate that pharmacological enhancement of α7 nAChRs function could be a potential therapeutic route to alleviate disease-related cognitive deficits. A recent pharmacological approach adopted to increase α7 nAChR activity has been to identify selective positive allosteric modulators (PAMs). α7 nAChR PAMs have been divided into two classes: type I PAMs increase agonist potency with only subtle effects on kinetics, whereas type II agents produce additional dramatic effects on desensitization and deactivation kinetics. Here we report novel observations concerning the pharmacology of the canonical type II PAM, PNU120596. Using patch clamp analysis of acetylcholine (ACh)-mediated currents through recombinant rat α7 nAChR we show that positive allosteric modulation measured in two different ways is greatly attenuated when the temperature is raised to near physiological levels. Furthermore, PNU120596 largely removes the strong inward rectification usually exhibited by α7 nAChR-mediated responses.
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Vol. 2, article 81
Place of publication