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dc.contributor.author
Yévenes, Gonzalo E.
dc.contributor.author
Zeilhofer, Hanns U.
dc.date.accessioned
2018-07-26T11:21:14Z
dc.date.available
2017-06-09T13:33:37Z
dc.date.available
2018-07-26T11:21:14Z
dc.date.issued
2011-08-25
dc.identifier.issn
1932-6203
dc.identifier.other
10.1371/journal.pone.0023886
en_US
dc.identifier.uri
http://hdl.handle.net/20.500.11850/39367
dc.identifier.doi
10.3929/ethz-b-000039367
dc.description.abstract
Glycine receptors (GlyRs) are transmitter-gated anion channels of the Cys-loop superfamily which mediate synaptic inhibition at spinal and selected supraspinal sites. Although they serve pivotal functions in motor control and sensory processing, they have yet to be exploited as drug targets partly because of hitherto limited possibilities for allosteric control. Endocannabinoids (ECs) have recently been characterized as direct allosteric GlyR modulators, but the underlying molecular sites have remained unknown. Here, we show that chemically neutral ECs (e.g. anandamide, AEA) are positive modulators of α1, α2 and α3 GlyRs, whereas acidic ECs (e.g. N-arachidonoyl-glycine; NA-Gly) potentiate α1 GlyRs but inhibit α2 and α3. This subunit-specificity allowed us to identify the underlying molecular sites through analysis of chimeric and mutant receptors. We found that alanine 52 in extracellular loop 2, glycine 254 in transmembrane (TM) region 2 and intracellular lysine 385 determine the positive modulation of α1 GlyRs by NA-Gly. Successive substitution of non-conserved extracellular and TM residues in α2 converted NA-Gly-mediated inhibition into potentiation. Conversely, mutation of the conserved lysine within the intracellular loop between TM3 and TM4 attenuated NA-Gly-mediated potentiation of α1 GlyRs, without affecting inhibition of α2 and α3. Notably, this mutation reduced modulation by AEA of all three GlyRs. These results define molecular sites for allosteric control of GlyRs by ECs and reveal an unrecognized function for the TM3-4 intracellular loop in the allosteric modulation of Cys-loop ion channels. The identification of these sites may help to understand the physiological role of this modulation and facilitate the development of novel therapeutic approaches to diseases such as spasticity, startle disease and possibly chronic pain.
en_US
dc.format
application/pdf
en_US
dc.language.iso
en
en_US
dc.publisher
Public Library of Science
en_US
dc.rights.uri
http://creativecommons.org/licenses/by/3.0/
dc.title
Molecular Sites for the Positive Allosteric Modulation of Glycine Receptors by Endocannabinoids
en_US
dc.type
Journal Article
dc.rights.license
Creative Commons Attribution 3.0 Unported
ethz.journal.title
PLoS ONE
ethz.journal.volume
6
en_US
ethz.journal.issue
8
en_US
ethz.journal.abbreviated
PLoS ONE
ethz.pages.start
e23886
en_US
ethz.size
14 p.
en_US
ethz.version.deposit
publishedVersion
en_US
ethz.identifier.wos
ethz.identifier.nebis
006206116
ethz.publication.place
Lawrence, Kan.
en_US
ethz.publication.status
published
en_US
ethz.leitzahl
ETH Zürich::00002 - ETH Zürich::00012 - Lehre und Forschung::00007 - Departemente::02020 - Dep. Chemie und Angewandte Biowiss. / Dep. of Chemistry and Applied Biosc.::02534 - Institut für Pharmazeutische Wiss. / Institute of Pharmaceutical Sciences::03742 - Zeilhofer, Hanns U. / Zeilhofer, Hanns U.
en_US
ethz.leitzahl.certified
ETH Zürich::00002 - ETH Zürich::00012 - Lehre und Forschung::00007 - Departemente::02020 - Dep. Chemie und Angewandte Biowiss. / Dep. of Chemistry and Applied Biosc.::02534 - Institut für Pharmazeutische Wiss. / Institute of Pharmaceutical Sciences::03742 - Zeilhofer, Hanns U. / Zeilhofer, Hanns U.
ethz.date.deposited
2017-06-09T13:33:45Z
ethz.source
ECIT
ethz.identifier.importid
imp59364e60cbac429624
ethz.ecitpid
pub:63375
ethz.eth
yes
en_US
ethz.availability
Open access
en_US
ethz.rosetta.installDate
2017-07-19T08:23:34Z
ethz.rosetta.lastUpdated
2018-11-07T17:25:36Z
ethz.rosetta.versionExported
true
ethz.COinS
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