NDLI: Additional Acetylcholine (ACh) Binding Site at α4/α4 Interface of (α4β2)2α4 Nicotinic Receptor Influences Agonist Sensitivity*

Content Provider	PubMed Central
Author	Mazzaferro, Simone Benallegue, Naïl Carbone, Anna Gasparri, Federica Vijayan, Ranjit Biggin, Philip C. Moroni, Mirko Bermudez, Isabel
Copyright Year	2011
Abstract	Nicotinic acetylcholine receptor (nAChR) α4 and β2 subunits assemble in two alternate stoichiometries to produce (α4β2)2α4 and (α4β2)2β2, which display different agonist sensitivities. Functionally relevant agonist binding sites are thought to be located at α4(+)/β2(−) 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 α4 or β2 as auxiliary subunits produces isoform-specific α4(+)/α4(−) or β2(+)/β2(−) interfaces. Using fully concatenated (α4β2)2α4 nAChRs in conjunction with structural modeling, chimeric receptors, and functional mutagenesis, we have identified an additional site at the α4(+)/α4(−) interface that accounts for isoform-specific agonist sensitivity of the (α4β2)2α4 nAChR. The additional site resides in a region that also contains a potentiating Zn2+ site but is engaged by agonists to contribute to receptor activation. By engineering α4 subunits to provide a free cysteine in loop C at the α4(+)α4(−) 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 α4(+)/(α4(−) interface leads to channel gating through a coupling mechanism involving loop C. Overall, we propose that the additional agonist site at the α4(+)/α4(−) interface, when occupied by agonist, contributes to receptor activation and that this additional contribution underlies the agonist sensitivity signature of (α4β2)2α4 nAChRs.
Related Links	http://dx.doi.org/10.1074/jbc.m111.262014
Ending Page	31054
Page Count	12
Starting Page	31043
File Format	PDF
ISSN	00219258
e-ISSN	1083351X
Journal	The Journal of Biological Chemistry
Issue Number	35
Volume Number	286
Language	English
Publisher	American Society for Biochemistry and Molecular Biology
Publisher Date	2011-09-02
Access Restriction	Open
Rights Holder	American Society for Biochemistry and Molecular Biology
Subject Keyword	Cell Biology Biochemistry Molecular Biology Research in Higher Education
Content Type	Text
Resource Type	Article
Subject	Cell Biology Biochemistry Molecular Biology

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