Click here to close
Hello! We notice that you are using Internet Explorer, which is not supported by Xenbase and may cause the site to display incorrectly.
We suggest using a current version of Chrome,
FireFox, or Safari.
Additional acetylcholine (ACh) binding site at alpha4/alpha4 interface of (alpha4beta2)2alpha4 nicotinic receptor influences agonist sensitivity.
Mazzaferro S
,
Benallegue N
,
Carbone A
,
Gasparri F
,
Vijayan R
,
Biggin PC
,
Moroni M
,
Bermudez I
.
???displayArticle.abstract???
Nicotinic acetylcholine receptor (nAChR) α4 and β2 subunits assemble in two alternate stoichiometries to produce (α4β2)(2)α4 and (α4β2)(2)β2, 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)(2)α4 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)(2)α4 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 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)(2)α4 nAChRs.
Akk,
Activation of muscle nicotinic acetylcholine receptor channels by nicotinic and muscarinic agonists.
1999, Pubmed
Akk,
Activation of muscle nicotinic acetylcholine receptor channels by nicotinic and muscarinic agonists.
1999,
Pubmed
Akk,
Aromatics at the murine nicotinic receptor agonist binding site: mutational analysis of the alphaY93 and alphaW149 residues.
2001,
Pubmed
Brams,
Crystal structures of a cysteine-modified mutant in loop D of acetylcholine-binding protein.
2011,
Pubmed
Bren,
Identification of residues in the adult nicotinic acetylcholine receptor that confer selectivity for curariform antagonists.
1997,
Pubmed
Campos-Caro,
A single residue in the M2-M3 loop is a major determinant of coupling between binding and gating in neuronal nicotinic receptors.
1996,
Pubmed
,
Xenbase
Carbone,
Pentameric concatenated (alpha4)(2)(beta2)(3) and (alpha4)(3)(beta2)(2) nicotinic acetylcholine receptors: subunit arrangement determines functional expression.
2009,
Pubmed
,
Xenbase
Castaldo,
A novel hyperekplexia-causing mutation in the pre-transmembrane segment 1 of the human glycine receptor alpha1 subunit reduces membrane expression and impairs gating by agonists.
2004,
Pubmed
Gay,
Gating of nicotinic ACh receptors; new insights into structural transitions triggered by agonist binding that induce channel opening.
2007,
Pubmed
Gotti,
Neuronal nicotinic receptors: from structure to pathology.
2004,
Pubmed
Groot-Kormelink,
Incomplete incorporation of tandem subunits in recombinant neuronal nicotinic receptors.
2004,
Pubmed
,
Xenbase
Hansen,
Galanthamine and non-competitive inhibitor binding to ACh-binding protein: evidence for a binding site on non-alpha-subunit interfaces of heteromeric neuronal nicotinic receptors.
2007,
Pubmed
Hansen,
Structures of Aplysia AChBP complexes with nicotinic agonists and antagonists reveal distinctive binding interfaces and conformations.
2005,
Pubmed
Hsiao,
Zinc potentiates neuronal nicotinic receptors by increasing burst duration.
2008,
Pubmed
,
Xenbase
Hu,
Arginine 222 in the pre-transmembrane domain 1 of 5-HT3A receptors links agonist binding to channel gating.
2003,
Pubmed
Iturriaga-Vásquez,
Molecular determinants for competitive inhibition of alpha4beta2 nicotinic acetylcholine receptors.
2010,
Pubmed
,
Xenbase
Kuryatov,
Nicotine acts as a pharmacological chaperone to up-regulate human alpha4beta2 acetylcholine receptors.
2005,
Pubmed
Lee,
Principal pathway coupling agonist binding to channel gating in nicotinic receptors.
2005,
Pubmed
Maskos,
Nicotine reinforcement and cognition restored by targeted expression of nicotinic receptors.
2005,
Pubmed
Moroni,
alpha4beta2 nicotinic receptors with high and low acetylcholine sensitivity: pharmacology, stoichiometry, and sensitivity to long-term exposure to nicotine.
2006,
Pubmed
,
Xenbase
Moroni,
Non-agonist-binding subunit interfaces confer distinct functional signatures to the alternate stoichiometries of the alpha4beta2 nicotinic receptor: an alpha4-alpha4 interface is required for Zn2+ potentiation.
2008,
Pubmed
,
Xenbase
Mukhtasimova,
Detection and trapping of intermediate states priming nicotinic receptor channel opening.
2009,
Pubmed
Mukhtasimova,
Initial coupling of binding to gating mediated by conserved residues in the muscle nicotinic receptor.
2005,
Pubmed
Nelson,
Alternate stoichiometries of alpha4beta2 nicotinic acetylcholine receptors.
2003,
Pubmed
,
Xenbase
Perkins,
Loop 2 structure in glycine and GABA(A) receptors plays a key role in determining ethanol sensitivity.
2009,
Pubmed
,
Xenbase
Purohit,
Acetylcholine receptor gating: movement in the alpha-subunit extracellular domain.
2007,
Pubmed
Rayes,
Number and locations of agonist binding sites required to activate homomeric Cys-loop receptors.
2009,
Pubmed
Rogers,
Benzodiazepine and beta-carboline regulation of single GABAA receptor channels of mouse spinal neurones in culture.
1994,
Pubmed
Son,
Nicotine normalizes intracellular subunit stoichiometry of nicotinic receptors carrying mutations linked to autosomal dominant nocturnal frontal lobe epilepsy.
2009,
Pubmed
Tapia,
Ca2+ permeability of the (alpha4)3(beta2)2 stoichiometry greatly exceeds that of (alpha4)2(beta2)3 human acetylcholine receptors.
2007,
Pubmed
,
Xenbase
Unwin,
Refined structure of the nicotinic acetylcholine receptor at 4A resolution.
2005,
Pubmed
Venkatachalan,
A conserved salt bridge critical for GABA(A) receptor function and loop C dynamics.
2008,
Pubmed
,
Xenbase
Wang,
Single-channel current through nicotinic receptor produced by closure of binding site C-loop.
2009,
Pubmed
Xiu,
A unified view of the role of electrostatic interactions in modulating the gating of Cys loop receptors.
2005,
Pubmed
,
Xenbase
Xiu,
Nicotine binding to brain receptors requires a strong cation-pi interaction.
2009,
Pubmed
,
Xenbase
Zwart,
Sazetidine-A is a potent and selective agonist at native and recombinant alpha 4 beta 2 nicotinic acetylcholine receptors.
2008,
Pubmed
,
Xenbase