Acetylcholine Receptor: An Allosteric Protein
SciencePublished 21 September 1984
Jean‐Pierre Changeux, Anne Devillers‐Thiéry, Phillippe Chemouilli
Citations622
SJR quartileQ1
SJR score10.42
SNIP6.62
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Abstract
The nicotine receptor for the neurotransmitter acetylcholine is an allosteric protein composed of four different subunits assembled in a transmembrane pentamer alpha 2 beta gamma delta. The protein carries two acetylcholine sites at the level of the alpha subunits and contains the ion channel. The complete sequence of the four subunits is known. The membrane-bound protein undergoes conformational transitions that regulate the opening of the ion channel and are affected by various categories of pharmacologically active ligands.
Keywords
Biochemistry, Genetics and Molecular Biology
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1,462 Citations1957B. Katz, S. Thesleff
ScienceAutoimmune Response to Acetylcholine Receptor
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773 Citations1979D M Fambrough
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528 Citations1983Masaharu Noda, Hideo Takahashi +9 more
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432 Citations1983Masaharu Noda, Yasuji Furutani +9 more
Nucleotide sequence analysis of the cloned DNAs has revealed the primary structures of the calf and human AChR α-subunit precursors, which exhibit marked sequence homology with their Torpedo counterpart.
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406 Citations1971Ricardo Miledi, P B Molinoff +1 more
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397 Citations1976H C Fertuck, MM Salpeter
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382 Citations1978Jacqueline A. Reynolds, Arthur Karlin
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375 Citations1977André Sobel, Michel Weber +1 more
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335 Citations1975Stephen W. Kuffler, Doju Yoshikami
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Biophysical JournalA structural model of the acetylcholine receptor channel based on partition energy and helix packing calculations
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BiochemistryMultiple sites of action for noncompetitive blockers on acetylcholine receptor rich membrane fragments from Torpedo marmorata
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The dose-response curves to cholinergic agents obtained in vitro agree, quantitatively, with the dose- response curves recorded in vivo by electrophysiological methods.
BiochemistryEquilibrium binding of [3H]tubocurarine and [3H]acetylcholine by torpedo postsynaptic membranes: stoichiometry and ligand interactions
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Journal of Biological ChemistryThe Acetylcholine Receptor
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The toxin-receptor equilibrium and the DEAE-filter paper assay provide a convenient method for studying the interaction of receptor with cholinergic ligands.
Biochemical and Biophysical Research CommunicationsAffinity-labeling of purified acetylcholine receptor from Torpedo californica
244 Citations1974Cheryl L. Weill, Mark G. McNamee +1 more
The receptor for acetylcholine purified from electric tissue of Torpedo californica has been assayed both by affinity-alkylation and by neurotoxin binding, resulting in the exclusive labeling of the 39,000 dalton subunit.
European Journal of BiochemistryPurification and Properties of the Cholinergic Receptor Protein from Electrophorus electricus Electric Tissue
240 Citations1974Jean‐Claude Meunier, Robert Sealock +2 more
The acetylcholine (nicotinic) receptor from the electric organ of Electrophorus electricus has been purified approx.
BiochemistryBiochemical properties of acetylcholine receptor subunits from Torpedo californica
236 Citations1979Jon Lindstrom, John P. Merlie +1 more
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228 Citations1977Paul R. Adams
In the presence of procaine the suberyldicholine‐evoked conductance first rapidly decreases and then slowly increases following a hyperpolarizing step, but the fast relaxation has a time constant of ∼ 1 msec, and the slow relaxation a time constants of 10‐150 msec.
The Journal of PhysiologyThe charge carried by single‐channel currents of rat cultured muscle cells in the presence of local anaesthetics.
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The simple sequential model of channel blockade does not apply for concentrations of QX222 higher than 40 microM, and the distribution of gap times within a burst could not be fitted by a single exponential for high concentrations ofQX222.
Proceedings of the National Academy of SciencesPhotochromic Activators of the Acetylcholine Receptor
211 Citations1971Eva Bartels, N. H. Wassermann +1 more
Two photochromic activators of the electrogenic membrane of the electroplax of Electrophorus electricus are described and the possibility of using trans-Bis-Q and trans-QBr to characterize and isolate the receptor protein is discussed.
The Journal of PhysiologySubstance P reduces acetylcholine‐induced currents in isolated bovine chromaffin cells.
208 Citations1984David E. Clapham, Erwin Neher
It is concluded that substance P inhibits ACh‐induced depolarization of chromaffin cells either by increasing the rate of desensitization or by inducing channel blockade, which indirectly enhances desensitized cells.
CellCrosslinking of proteins in acetylcholine receptor-rich membranes: Association between the β-subunit and the 43 kd subsynaptic protein
199 Citations1983Steven J. Burden, R.L. Depalma +1 more
The 43 kd protein is intimately associated with the AChR and in close proximity to the beta-subunit and the composition of crosslinked products was determined by Western blots and monoclonal antibodies.
NatureActive multi-subunit ACh receptor assembled by translation of heterologous mRNA in Xenopus oocytes
195 Citations1981K Sumikawa, Michael Houghton +3 more
It is reported here that Xenopus oocytes efficiently assemble intact, multi-subunit AChR molecules which show properties characteristic of the native A ChR, including the binding of α-bungarotoxin (α-BTX).
BiochemistryStudies of the composition of purified Torpedo californica acetylcholine receptor and of its subunits
193 Citations1979Richard Vandlen, Wilson C.‐S. Wu +2 more
It is concluded that the receptor contains O-phosphoserine residues to the extent of approximately seven residues per molecule and these residues occur in all constituent polypeptides.
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BiochemistryLipid-protein interactions in reconstituted membranes containing acetylcholine receptor
188 Citations1983Jeffrey F. Ellena, Michael A. Blazing +1 more
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Proceedings of the National Academy of SciencescAMP-dependent protein kinase phosphorylates the nicotinic acetylcholine receptor
187 Citations1983Richard L. Huganir, Paul Greengard
Results are consistent with the idea that the acetylcholine receptor is phosphorylated in vivo by a cAMP-dependent protein kinase.
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184 Citations1977Michael J. Ross, Michael W. Klymkowsky +2 more
Membranes prepared from Torpedo californica electroplax containing acctylcholine receptors have been studied by X-ray diffraction and electron microscopy and Sharp maxima in the scattering pattern indicate that long stretches of secondary structure are present in the receptor-containing membranes.
BiochemistryMolecular forms of acetylcholine receptor. Effects of calcium ions and a sulfhydryl reagent on the occurrence of oligomers
184 Citations1977Hai Won Chang, Ernest Bock
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184 Citations1977Alfred Maelicke, Bernard W. Fulpius +2 more
Journal of Biological ChemistryPurification of acetylcholine receptors, reconstitution into lipid vesicles, and study of agonist-induced cation channel regulation.
181 Citations1980J Lindström, Robert R. H. Anholt +4 more
It is demonstrated that only one of the two toxin binding sites on the receptor monomer, the one which can be affinity alkylated with 4-(N-maleimido)benzyltrimethylammonium, controls the carbamylcholine-induced opening of the cation channel.
BiochemistryPurification of acetylcholine receptors from Torpedo claifornica electroplax by affinity chromatography
178 Citations1973J. Schmidt, Michael A. Raftery
Biochemical JournalPurification of <i>Torpedo californica</i> post-synaptic membranes and fractionation of their constituent proteins
177 Citations1980Janet Elliott, Steven G. Blanchard +7 more
A rapid methof for preparation of membrane fractions highly enriched in nicotinic acetylcholine receptor from Torpedo californica electroplax is described, which yields solubilized receptor preparations comparable with the most highly purified protein obtained by affinity-chromatographic procedures.
Nucleic Acids ResearchThe molecular cloning and characterisation of cDNA coding for the α subunit of the acetyl-choline receptor
175 Citations1982K Sumikawa, Michael Houghton +4 more
DNA sequence analysis has enabled the elucidation of a large part of the polypeptide primary sequence which is discussed in relation to its acetylcholine binding activity and the location of receptor within the plasma membrane.
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174 Citations1978Max Epstein, E. Racker
Membranes rich in acetylcholine receptor were isolated from Torpedo californica by a modification of the procedure of Sobel et al. and exhibited a rapid, carbamylch Caroline-dependent uptake of 22Na+, which was inhibited by alpha-bungarotoxin and several other known inhibitors.
PubMedBinding of Naja nigricollis (3H)alpha-toxin to membrane fragments from Electrophorus and Torpedo electric organs. I. Binding of the tritiated alpha-neurotoxin in the absence of effector.
172 Citations1974Michel Weber, Jean‐Pierre Changeux
Isotopic dilution and pharmacological experiments showed that the tritiated α-toxin behaved exactly like the native, unlabelled compound.
BiochemistrySingle-channel recordings from purified acetylcholine receptors reconstituted in bilayers formed at the tip of patch pipets
172 Citations1983Benjamín A. Suárez‐Isla, Kee Wan +2 more
The results suggest that the full cycle of solubilization, purification, and reconstitution of this membrane receptor can be achieved without impairment of channel function.
BiochemistryPermeability control by cholinergic receptors in Torpedo postsynaptic membranes: agonist dose-response relations measured at second and millisecond times
170 Citations1980Richard R. Neubig, Jonathan B. Cohen
A quantitative analysis of nicotine acetylcholine receptor function in Torpedo postsynaptic membranes is presented and a model is proposed to account for both binding and response.
Proceedings of the National Academy of SciencesRegulation of binding properties of the nicotinic receptor protein by cholinergic ligands in membrane fragments from Torpedo marmorata.
169 Citations1975Michel Weber, T David-Pfeuty +1 more
It is proposed that, in the membrane at rest, the receptor protein is present under a state of low affinity for agonists and that the reversible stabilization by the agonists of a high affinity state corresponds to the "pharmacological desensitization" of the system as predicted by one of the models of Katz and Thesleff.
Proceedings of the National Academy of SciencesDecamethonium both opens and blocks endplate channels.
169 Citations1978Paul R. Adams, Bert Sakmann
Three types of experiments revealed two kinetic processes controlling the opening of endplate channels, one that reflects agonist action and another that reflects local anesthetic-like blocking activity in decamethonium action.
The Journal of PhysiologyA study of desensitization of acetylcholine receptors using nerve‐released transmitter in the frog
169 Citations1981Karl L. Magleby, B S Pallotta
Desensitization of acetylcholine (ACh) receptors was studied at the frog neuromuscular junction under voltage clamp under Voltage clamp in 1.1.
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165 Citations1984Robert Sealock, B E Wray +1 more
Results show that the 43K protein is a receptor-specific protein having a restricted spatial relationship to the membrane, and support models in which the 43k protein is associated with the cytoplasmic domains of the receptor molecule.
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163 Citations1978Vinayak N. Damle, Arthur Karlin
Proceedings of the National Academy of SciencesReduction and specific alkylation of the receptor for acetylcholine.
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Proceedings of the National Academy of SciencesFunctional acetylcholine receptor from Torpedo marmorata in planar membranes.
151 Citations1980H. Schindler, Ulrich Quast
The ratio of observed channels to alpha-bungarotoxin sites present showed that a significant fraction of acetylcholine receptor in the membrane was functional and the quantitative aspects of the cation channel, the desensitization, and the ligand binding properties were in close agreement with established values.
Journal of Molecular BiologyImmunospecific identification and three-dimensional structure of a membrane-bound acetylcholine receptor from Torpedo californica
151 Citations1979Michael W. Klymkowsky, Robert M. Stroud
Calculated molecular volumes based on X-ray diffraction and electron microscopy indicate that the membrane receptor has a molecular weight in the range of 250,000 to 310,000, a range consistent with current estimates of detergent-solubilized monomer molecular weight.
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146 Citations1981David J. Anderson, Günter Blobel
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It is proposed to-day to consider what is the actual seat of certain physiological activities in cells, and chiefly in those of muscular and nervous tissues, in the body.
The Journal of General PhysiologyAlteration by Xylocaine (Lidocaine) and Its Derivatives of the Time Course of the End Plate Potential
141 Citations1968Alan Steinbach
Clear structure-activity relations indicate that the receptor to which the drugs bind to produce the prolonged response can be the receptor for acetylcholine, and shows that the effects of Xylocaine depend on the time course of receptor activation and are quite different from the effect of d-tubocurarine.
Proceedings of the National Academy of SciencesReconstitution of purified acetylcholine receptors with functional ion channels in planar lipid bilayers.
139 Citations1980Nathan Nelson, Robert R. H. Anholt +2 more
Pro purified acetylcholine receptor reconstituted into lipid bilayers exhibited the pharmacological specificity, activation, and desensitization properties expected of this receptor in native membranes.
BiochemistryKinetics of binding of [3H]acetylcholine and [3H]carbamoylcholine to Torpedo postsynaptic membranes: slow conformational transitions of the cholinergic receptor
139 Citations1980Norman D. Boyd, Jonathan B. Cohen
The results are further discussed in terms of alternate less satisfactory reaction models and are compared with the receptor conformational equilibria deduced by the use of other kinetic techniques.
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137 Citations1980Steven M. Sine, Palmer Taylor
The decrement in functional capacity of the nicotinic receptor on intact BC3H-1 cells has been simultaneously compared with the fractional occupation of the receptor by cobra alpha-toxin and a scheme for desensitization of the receptors is presented which incorporates both nonequivalence in the two agonist binding-sites and the maintenance of symmetry in the receptor states undergoing transitions.
BiochemistryConformations of Torpedo acetylcholine receptor associated with ion transport and desensitization
134 Citations1982Richard R. Neubig, Norman D. Boyd +1 more
Proceedings of the National Academy of SciencesThe Affinity-Labeling of Partially Purified Acetylcholine Receptor from Electric Tissue of <i>Electrophorus</i>
134 Citations1973Arthur Karlin, David Cowburn
The receptor for acetylcholine was partially purified by affinity chromatography of an extract in Triton X-100 of membrane fragments from electric tissue by reaction with the affinity-alkylating agent, [methyl-(3)H]4-(N-maleimido)-benzyltrimethylammonium iodide.
BiochemistryFractionation and partial characterization of membrane particles from Torpedo californica electroplax
133 Citations1973J R Duguid, Michael A. Raftery
European Journal of BiochemistryMembranes Rich in Acetylcholine Receptor: Characterization and Reconstitution to Excitable Membranes from Exogenous Lipids
132 Citations1978W Schiebler, Ferdinand Hucho
Characterization of acetylcholine-receptor-enriched membranes from Torpedo californica electric tissue by negative-staining electron-microscopy and by lipid analysis is described, which shows a lower protein/lipid ratio and a lower phosphatidyl choline/sphingomyelin ratio as compared to 46%/7% for the receptor-en enriched membranes.
Biophysical JournalActivation of a nicotinic acetylcholine receptor
130 Citations1984Steven M. Sine, Joe Henry Steinbach
It is concluded that there are two open states of the ACh receptor with different mean open times and that a single receptor may open to either open state and the existence of a second closed-channel state coupled to the open state is postulated.
Journal of Cell ScienceA morphological study of the cholinergic receptor protein from <i>Torpedo marmorata</i> in its membrane environment and in its detergent-extracted purified form
129 Citations1978Jean Cartaud, E. L. Benedetti +2 more
Journal of Biological ChemistryRestoration of 125I-alpha-bungarotoxin binding activity to the alpha subunit of Torpedo acetylcholine receptor isolated by gel electrophoresis in sodium dodecyl sulfate.
129 Citations1981John G. Haggerty, Stanley C. Froehner
Results indicate that at least part of the alpha-bungarotoxin binding site resides on the alpha subunit, which is consistent with the findings of previous work on acetylcholine receptor isolation.
Molecular PharmacologyIdentification of a Local Anesthetic Binding Site in Nicotinic Post-Synaptic Membranes Isolated from Torpedo marmorata Electric Tissue
123 Citations1979Elizabeth K. Krodel, Robert A. Beckman +1 more
It is concluded that there is a specific site of binding for the aromatic amine non-competitive antagonists in the isolated nicotinic post-synaptic membrane that is distinct from the site ofbinding of acetylcholine.
NatureIn vitro phosphorylation of the acetylcholine receptor
122 Citations1977Vivian I. Teichberg, André Sobel +1 more
In detergent extracts of membrane fragments isolated from the electric organ of E. electricus, a phosphorylation of AChR takes place when incubated in the presence of γ-32P-ATP, Mn2+ and the endogenous protein kinases.
ScienceAcetylcholine Receptor: Covalent Attachment of Depolarizing Groups at the Active Site
121 Citations1969Israel Silman, Arthur Karlin
Following reduction of the acetylcholine receptor in the electroplax with dithiothreitol, the quaternary ammonium compounds bromoacetyl choline bromide and the p-nitrophenyl ester of (p-carboxyphenyl) trimethylammonium iodide react near the active site probably with a sulfhydryl group.
Brain ResearchUltrastructure of isolated membranes ofTorpedo electric tissue
121 Citations1973E. Nickel, Lincoln T. Potter
Proceedings of the National Academy of SciencesSubstance P enhances cholinergic receptor desensitization in a clonal nerve cell line.
120 Citations1980W B Stallcup, J Patrick
Substance P inhibits carbamylcholine-induced 22Na+ uptake in the clonal cell line PC12 and may modulate the activity of the receptor-ionophore complex by binding to a distinct regulatory site, which does not require open ion channels for binding.
European Journal of BiochemistryTransmembrane Orientation of Proteins Present in Acetylcholine Receptor‐Rich Membranes from <i>Torpedo marmorata</i> Studied by Selective Proteolysis
119 Citations1980Lawrence P. Wennogle, Jean‐Pierre Changeux
The transmembrane orientation of the polypeptide chains present in acetylcholine receptor-rich membranes from Torpedo marmorata was studied by selective proteolysis and it was concluded that the 43000-Mr polyPEptide is entirely enclosed by the lipid bilayer.
The Journal of Cell BiologyConsequences of alkaline treatment for the ultrastructure of the acetylcholine-receptor-rich membranes from Torpedo marmorata electric organ.
119 Citations1981Jean Cartaud, A Sobel +3 more
These results are interpreted in terms of a structural stabilization and immobilization of the AchR by the 43,000- Mr protein binding to the inner face of the subsynaptic membrane.
Journal of Biological ChemistryMonoclonal antibodies to cytoplasmic domains of the acetylcholine receptor.
118 Citations1983Stanley C. Froehner, Karen Douville +2 more
Fourteen clonal hybridoma lines that secrete monoclonal antibodies (mabs) to the Torpedo acetylcholine receptor (AChR) have been isolated and their reactivities were analyzed by an immunoreplica technique and included mabs that are unable to bind the membrane-associated AChR.
NatureRegulation of muscle acetylcoline receptor synthesis in vitro by cyclic nucleotide derivatives
117 Citations1979Heinrich Betz, Jean‐Pierre Changeux
It is shown that the synthesis of AChR in cultured embryonic myotubes is modified by cyclic nucleotide derivatives, and it is suggested that cyclicucleotides may serve as intracellular signals15 in both activity-mediated and neurotrophic control of extrasynaptic AChr synthesis.
Molecular PharmacologyEffects of Local Anesthetics and Calcium on the Interaction of Cholinergic Ligands with the Nicotinic Receptor Protein from Torpedo marmorata
117 Citations1974Jonathan B. Cohen, Michel Weber +1 more
Fluorescence and radioactive ligand assays demonstrate that Ca++ also causes an increase of receptor affinity for cholinergic ligands, but in a manner significantly different from that observed with local anesthetics.
BiochemistryOrganization of ligand binding sites at the acetylcholine receptor: a study with monoclonal antibodies
116 Citations1983Dianne Watters, Alfred Maelicke
A model of the organization of ligand binding sites at the receptor shows that either there exists separate sites for distinct groups of ligands within each of these binding regions or some ligands produce conformational changes of the receptor that reversibly abolish some antigenic sites.
Cold Spring Harbor Symposia on Quantitative BiologyThe Basal Lamina of the Neuromuscular Junction
116 Citations1983Joshua R. Sanes, Arlene Y. Chiu
Proceedings of the National Academy of SciencesUltraviolet light-induced labeling by noncompetitive blockers of the acetylcholine receptor from Torpedo marmorata.
114 Citations1981Robert E. Oswald, Jean‐Pierre Changeux
Data indicate a contribution of the delta chain to the binding site(s) of several well-characterized noncompetitive blockers and suggest that other receptor polypeptides may also contribute to this binding.
Journal of Biological ChemistryThe arrangement of the subunits of the acetylcholine receptor of Torpedo californica.
114 Citations1983Arthur Karlin, E Holtzman +4 more
Results indicate that the alpha chains are not contiguous and that neither the beta chain nor the delta chain lies between them, therefore, the arrangement of the chains most easily reconciled with assumptions and observations is alpha gamma alpha beta delta.
BiochemistryComparison of the subunits of Torpedo californica acetylcholine receptor by peptide mapping
114 Citations1979Stanley C. Froehner, Stein E. Rafto
The acetylcholine receptor from Torpedo californica electroplax was purified approximately 100-fold by affinity chromatography on alpha-neurotoxin-Sepharose 6B and the patterns of fragments generated by Staphylococcus aureus V8 protease, papain, or chymotrypsin were different for each of the polypeptides, suggesting that they are derivatives of each other.
Journal of Biological ChemistryLocal anesthetics and histrionicotoxin are allosteric inhibitors of the acetylcholine receptor. Studies of clonal muscle cells.
114 Citations1982Steven M. Sine, Palmer Taylor
Antagonism of the permeability response is compared with changes in agonist affinity induced by HTX, dibucaine, and QX314 and the parallel changes in both parameters indicate that the three inhibitors have similar mechanisms of action on the acetylcholine receptor in BC3H-1 cells.
Journal of Molecular BiologyStudies on the electrogenic action of acetylcholine with Torpedo marmorata electric organ
113 Citations1976Hans-Heinrich Grünhagen, Jean‐Pierre Changeux
It is concluded that binding of cholinergic ligands primarily increases the quantum yield of a fraction of bound quinacrine, which reflects a change of structure bearing a qualitative relationship to the pharmacological activity of the tested ligands.
BiochemistryRapid kinetics of agonist binding and permeability response analyzed in parallel on acetylcholine receptor rich membranes from Torpedo marmorata
109 Citations1983Thiérry Heidmann, Julius Bernhardt +2 more
Comparison of Dns-C6-Cho binding data with the permeability response to the same agonist demonstrates that the binding to the low-affinity conformation(s) of the acetylcholine receptor sites coincides with the triggering of the permeable increase--or "activation"--and the transitions to the intermediate- and high-Affinity states with the two-step process of channel closing-- or "desensitization".
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