Linked Life Data

19553237

Source:http://linkedlifedata.com/resource/pubmed/id/19553237

Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
3
pubmed:dateCreated
2009-8-24
pubmed:abstractText
M2-M3 linkers are receptor subunit domains known to be critical for the normal function of cysteine-loop ligand-gated ion channels. Previous studies of alpha and beta subunits of type "A" GABA receptors suggest that these linkers couple extracellular elements involved in GABA binding to the transmembrane segments that control the opening of the ion channel. To study the importance of the gamma subunit M2-M3 linker, we examined the macroscopic and single-channel effects of an engineered gamma2(L287A) mutation on GABA activation and propofol modulation. In the macroscopic analysis, we found that the gamma2(L287A) mutation decreased GABA potency but increased the ability of propofol to enhance both GABA potency and efficacy compared with wild-type receptors. Indeed, although propofol had significant effects on GABA potency in wild-type receptors, we found that propofol produced no corresponding increase in GABA efficacy. At the single-channel level, mutant receptors showed a loss in the longest of three open-time components compared with wild-type receptors under GABA activation. Furthermore, propofol reduced the duration of one closed-time component, increased the duration of two open-time components, and generated a third open component with a longer lifetime in mutant compared with wild-type receptors. Taken together, we conclude that although the gamma subunit is not required for the binding of GABA or propofol, the M2-M3 linker of this subunit plays a critical role in channel gating by GABA and allosteric modulation by propofol. Our results also suggest that in wild-type receptors, propofol exerts its enhancing effects by mechanisms extrinsic to channel gating.
pubmed:grant
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
pubmed:status
MEDLINE
pubmed:month
Sep
pubmed:issn
1521-0111
pubmed:author
pubmed:issnType
Electronic
pubmed:volume
76
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
641-51
pubmed:dateRevised
2010-11-18
pubmed:meshHeading
pubmed:year
2009
pubmed:articleTitle
Inverse effects on gating and modulation caused by a mutation in the M2-M3 Linker of the GABA(A) receptor gamma subunit.
pubmed:affiliation
Department of Anesthesiology, Emory University University School of Medicine, Atlanta, Georgia, USA. sean.oshea@mpibp-frankfurt.mpg.de
pubmed:publicationType
Journal Article, Research Support, N.I.H., Extramural