Linked Life Data

21757735

Source:http://linkedlifedata.com/resource/pubmed/id/21757735

Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
35
pubmed:dateCreated
2011-8-29
pubmed:abstractText
Nicotinic acetylcholine receptor (nAChR) ?4 and ?2 subunits assemble in two alternate stoichiometries to produce (?4?2)(2)?4 and (?4?2)(2)?2, which display different agonist sensitivities. Functionally relevant agonist binding sites are thought to be located at ?4(+)/?2(-) subunit interfaces, but because these interfaces are present in both receptor isoforms, it is unlikely that they account for differences in agonist sensitivities. In contrast, incorporation of either ?4 or ?2 as auxiliary subunits produces isoform-specific ?4(+)/?4(-) or ?2(+)/?2(-) interfaces. Using fully concatenated (?4?2)(2)?4 nAChRs in conjunction with structural modeling, chimeric receptors, and functional mutagenesis, we have identified an additional site at the ?4(+)/?4(-) interface that accounts for isoform-specific agonist sensitivity of the (?4?2)(2)?4 nAChR. The additional site resides in a region that also contains a potentiating Zn(2+) site but is engaged by agonists to contribute to receptor activation. By engineering ?4 subunits to provide a free cysteine in loop C at the ?4(+)?4(-) interface, we demonstrated that the acetylcholine responses of the mutated receptors are attenuated or enhanced, respectively, following treatment with the sulfhydryl reagent [2-(trimethylammonium)ethyl]methanethiosulfonate or aminoethyl methanethiosulfonate. The findings suggest that agonist occupation of the site at the ?4(+)/(?4(-) interface leads to channel gating through a coupling mechanism involving loop C. Overall, we propose that the additional agonist site at the ?4(+)/?4(-) interface, when occupied by agonist, contributes to receptor activation and that this additional contribution underlies the agonist sensitivity signature of (?4?2)(2)?4 nAChRs.
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
pubmed:status
MEDLINE
pubmed:month
Sep
pubmed:issn
1083-351X
pubmed:author
pubmed:issnType
Electronic
pubmed:day
2
pubmed:volume
286
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
31043-54
pubmed:meshHeading
pubmed:year
2011
pubmed:articleTitle
Additional acetylcholine (ACh) binding site at alpha4/alpha4 interface of (alpha4beta2)2alpha4 nicotinic receptor influences agonist sensitivity.
pubmed:affiliation
School of Life Sciences, Oxford Brookes University, Oxford OX3 0BP, United Kingdom.
pubmed:publicationType
Journal Article, Research Support, Non-U.S. Gov't