Single-channel and structural foundations of neuronal α7 acetylcholine receptor potentiation

Corrie J.P. daCosta, Chris R. Free, Jeremías Corradi, Cecilia Bouzat, Steven M. Sine

Research output: Contribution to journalArticlepeer-review

50 Scopus citations

Abstract

Potentiation of neuronal nicotinic acetylcholine receptors by exogenous ligands is a promising strategy for treatment of neurological disorders including Alzheimer's disease and schizophrenia. To gain insight into molecular mechanisms underlying potentiation, we examined ACh-induced single-channel currents through thehumanneuronal_7 acetylcholine receptor in the presence of the_7-specific potentiator PNU-120596 (PNU). Compared to the unusually brief single-channel opening episodes elicited by agonist alone, channel opening episodes in the presence of agonist and PNU are dramatically prolonged. Dwell time analysis reveals that PNU introduces two novel components into open time histograms, indicating at least two degrees of PNU-induced potentiation. Openings of the longest potentiated class coalesce into clusters whose frequency and duration change over a narrow range of PNU concentration. At PNU concentrations approaching saturation, these clusters last up to several minutes, prolonging the submillisecond_7 opening episodes by several orders of magnitude. Mutations known to reduce PNU potentiation at the whole-cell level still give rise to multisecond-long single-channel clusters. However mutation of five residues lining a cavity within each subunit's transmembrane domain abolishes PNU potentiation, defining minimal structural determinants of PNU potentiation.

Original languageEnglish (US)
Pages (from-to)13870-13879
Number of pages10
JournalJournal of Neuroscience
Volume31
Issue number39
DOIs
StatePublished - Sep 28 2011

ASJC Scopus subject areas

  • Neuroscience(all)

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