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Front Pharmacol. 2011 Dec 27;2:81. doi: 10.3389/fphar.2011.00081. eCollection 2011.

Voltage- and Temperature-Dependent Allosteric Modulation of α7 Nicotinic Receptors by PNU120596.

Author information

1
Pfizer Applied Neurophysiology Group, School of Physiology and Pharmacology, University of Bristol Bristol, UK.

Abstract

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.

KEYWORDS:

allosteric modulator; channel; electrophysiology; nicotinic receptors; patch clamp

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