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.
Br J Pharmacol
2005 Aug 01;1457:963-74. doi: 10.1038/sj.bjp.0706224.
Show Gene links
Show Anatomy links
Key roles of hydrophobic rings of TM2 in gating of the alpha9alpha10 nicotinic cholinergic receptor.
Plazas PV
,
De Rosa MJ
,
Gomez-Casati ME
,
Verbitsky M
,
Weisstaub N
,
Katz E
,
Bouzat C
,
Elgoyhen AB
.
???displayArticle.abstract???
We have performed a systematic mutagenesis of three hydrophobic rings (17', 13' and 9') within transmembrane region (TM) 2 of the alpha9alpha10 nicotinic cholinergic receptor (nAChR) to a hydrophilic (threonine) residue and compared the properties of mutant receptors reconstituted in Xenopus laevis oocytes. Phenotypic changes in alpha9alpha10 mutant receptors were evidenced by a decrease in the desensitization rate, an increase in both the EC(50) for ACh as well as the efficacy of partial agonists and the reduction of the allosteric modulation by extracellular Ca(2+). Mutated receptors exhibited spontaneous openings and, at the single-channel level, an increased apparent mean open time with no major changes in channel conductance, thus suggesting an increase in gating of the channel as the underlying mechanism. Overall, the degrees of the phenotypes of mutant receptors were more overt in the case of the centrally located V13'T mutant. Based on the atomic model of the pore of the electric organ of the Torpedo ray, we can propose that the interactions of side chains at positions 13' and 9' are key ones in creating an energetic barrier to ion permeation. In spite of the fact that the roles of the TM2 residues are mostly conserved in the distant alpha9alpha10 member of the nAChR family, their mechanistic contributions to channel gating show significant differences when compared to other nAChRs. These differences might be originated from slight differential intramolecular rearrangements during gating for the different receptors and might lead each nAChR to be in tune with their physiological roles.
Akabas,
Identification of acetylcholine receptor channel-lining residues in the entire M2 segment of the alpha subunit.
1994, Pubmed,
Xenbase
Akabas,
Identification of acetylcholine receptor channel-lining residues in the entire M2 segment of the alpha subunit.
1994,
Pubmed
,
Xenbase
Arellano,
A monovalent cationic conductance that is blocked by extracellular divalent cations in Xenopus oocytes.
1995,
Pubmed
,
Xenbase
Bertrand,
Unconventional pharmacology of a neuronal nicotinic receptor mutated in the channel domain.
1992,
Pubmed
,
Xenbase
Bertrand,
Stratification of the channel domain in neurotransmitter receptors.
1993,
Pubmed
Bertrand,
Paradoxical allosteric effects of competitive inhibitors on neuronal alpha7 nicotinic receptor mutants.
1997,
Pubmed
,
Xenbase
Bouzat,
Structural basis of the different gating kinetics of fetal and adult acetylcholine receptors.
1994,
Pubmed
Bouzat,
Subunit-selective contribution to channel gating of the M4 domain of the nicotinic receptor.
2002,
Pubmed
Chang,
Substitutions of the highly conserved M2 leucine create spontaneously opening rho1 gamma-aminobutyric acid receptors.
1998,
Pubmed
,
Xenbase
Chang,
Allosteric activation mechanism of the alpha 1 beta 2 gamma 2 gamma-aminobutyric acid type A receptor revealed by mutation of the conserved M2 leucine.
1999,
Pubmed
,
Xenbase
Colquhoun,
Binding, gating, affinity and efficacy: the interpretation of structure-activity relationships for agonists and of the effects of mutating receptors.
1998,
Pubmed
Corringer,
Mutational analysis of the charge selectivity filter of the alpha7 nicotinic acetylcholine receptor.
1999,
Pubmed
,
Xenbase
Cymes,
Structure of the transition state of gating in the acetylcholine receptor channel pore: a phi-value analysis.
2002,
Pubmed
Ebihara,
Xenopus connexin38 forms hemi-gap-junctional channels in the nonjunctional plasma membrane of Xenopus oocytes.
1996,
Pubmed
,
Xenbase
Elgoyhen,
Alpha 9: an acetylcholine receptor with novel pharmacological properties expressed in rat cochlear hair cells.
1994,
Pubmed
,
Xenbase
Elgoyhen,
alpha10: a determinant of nicotinic cholinergic receptor function in mammalian vestibular and cochlear mechanosensory hair cells.
2001,
Pubmed
,
Xenbase
England,
Backbone mutations in transmembrane domains of a ligand-gated ion channel: implications for the mechanism of gating.
1999,
Pubmed
,
Xenbase
Filatov,
The role of conserved leucines in the M2 domain of the acetylcholine receptor in channel gating.
1995,
Pubmed
,
Xenbase
Galzi,
Mutations in the channel domain of a neuronal nicotinic receptor convert ion selectivity from cationic to anionic.
1992,
Pubmed
,
Xenbase
Galzi,
The multiple phenotypes of allosteric receptor mutants.
1996,
Pubmed
Galzi,
Identification of calcium binding sites that regulate potentiation of a neuronal nicotinic acetylcholine receptor.
1996,
Pubmed
,
Xenbase
Grigoriev,
The effects of level of expression of a jellyfish Shaker potassium channel: a positive potassium feedback mechanism.
1999,
Pubmed
,
Xenbase
Hamill,
Multiple conductance states of single acetylcholine receptor channels in embryonic muscle cells.
1981,
Pubmed
Karlin,
Toward a structural basis for the function of nicotinic acetylcholine receptors and their cousins.
1995,
Pubmed
Katz,
High calcium permeability and calcium block of the alpha9 nicotinic acetylcholine receptor.
2000,
Pubmed
,
Xenbase
Labarca,
Channel gating governed symmetrically by conserved leucine residues in the M2 domain of nicotinic receptors.
1995,
Pubmed
,
Xenbase
Le Novère,
Molecular evolution of the nicotinic acetylcholine receptor: an example of multigene family in excitable cells.
1995,
Pubmed
Le Novère,
The diversity of subunit composition in nAChRs: evolutionary origins, physiologic and pharmacologic consequences.
2002,
Pubmed
Miyazawa,
Structure and gating mechanism of the acetylcholine receptor pore.
2003,
Pubmed
Panicker,
Evidence for a centrally located gate in the pore of a serotonin-gated ion channel.
2002,
Pubmed
,
Xenbase
Papke,
An evaluation of neuronal nicotinic acetylcholine receptor activation by quaternary nitrogen compounds indicates that choline is selective for the alpha 7 subtype.
1996,
Pubmed
,
Xenbase
Rayes,
Molecular basis of the differential sensitivity of nematode and mammalian muscle to the anthelmintic agent levamisole.
2004,
Pubmed
Revah,
Mutations in the channel domain alter desensitization of a neuronal nicotinic receptor.
1991,
Pubmed
,
Xenbase
Taglietti,
A study of stretch-activated channels in the membrane of frog oocytes: interactions with Ca2+ ions.
1988,
Pubmed
Verbitsky,
Mixed nicotinic-muscarinic properties of the alpha9 nicotinic cholinergic receptor.
2000,
Pubmed
,
Xenbase
Weisstaub,
The alpha9alpha10 nicotinic acetylcholine receptor is permeable to and is modulated by divalent cations.
2002,
Pubmed
,
Xenbase
Wilson,
The location of the gate in the acetylcholine receptor channel.
1998,
Pubmed
