TY - JOUR
T1 - Single-channel and structural foundations of neuronal α7 acetylcholine receptor potentiation
AU - daCosta, Corrie J.P.
AU - Free, Chris R.
AU - Corradi, Jeremías
AU - Bouzat, Cecilia
AU - Sine, Steven M.
PY - 2011/9/28
Y1 - 2011/9/28
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=80053244433&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=80053244433&partnerID=8YFLogxK
U2 - 10.1523/JNEUROSCI.2652-11.2011
DO - 10.1523/JNEUROSCI.2652-11.2011
M3 - Article
C2 - 21957249
AN - SCOPUS:80053244433
SN - 0270-6474
VL - 31
SP - 13870
EP - 13879
JO - Journal of Neuroscience
JF - Journal of Neuroscience
IS - 39
ER -