期刊
NEUROPHARMACOLOGY
卷 107, 期 -, 页码 189-200出版社
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.neuropharm.2016.02.032
关键词
Cys-loop receptors; Nicotinic receptors; Patch-clamp; Single-channel recordings; Positive allosteric modulators
资金
- Universidad Nacional del Sur, Consejo Nacional de Investigaciones Cientificas y Tecnicas
- FONCYT
- Polish National Science Center [UMO-2013/09/D/NZ7/04549]
Enhancement of alpha 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-alpha 7 channel currents of representative members of each type and of less characterized compounds. Our results reveal that all PAMs enhance open-channel lifetime and produce episodes of successive openings, thus indicating that both types affect alpha 7 kinetics. Different PAM types show different sensitivity to temperature, suggesting different mechanisms of potentiation. By using a mutant alpha 7 receptor that is insensitive to the prototype type II PAM (PNU-120596), we show that some though not all type I PAMs share the structural determinants of potentiation. Overall, our study provides novel information on alpha 7 potentiation, which is key to the ongoing development of therapeutic compounds. (C) 2016 Elsevier Ltd. All rights reserved.
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