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- W2024170213 abstract "Acetylcholine receptor-channels (AChRs) mediate fast chemical transmission at the synapse. Agonist molecules, such as acetylcholine and nicotine, bind at two transmitter binding sites and trigger the channel to switch from a closed to an open conformation. At the synaptic cleft, acetylcholine is hydrolyzed by acetylcholinesterase to acetate and choline. Replacing an ester acetyl group by a hydroxyl group (from acetylcholine to choline) decreases the resting affinity by ∼50-fold and efficacy by ∼600-fold. To understand the action of these ligands and to design novel drugs, it is essential to measure both affinity and efficacy of agonist derivatives using wild type and binding-site mutated AChRs. A technical limitation is that agonists block the channel. Thus, experiments at high agonist concentrations, required due to a low affinity agonist or mutant, are difficult at −100 mV membrane potential. Using a background mutation and depolarization, we have developed an approach to measure AChR single-channel currents activated by various agonists without channel block even at concentrations >140 mM. Using this method, we have directly measured the efficacy of several derivatives of choline on the mouse neuromuscular AChR. Replacing the hydroxyl group of choline with different substituents, such as hydrogen, chloride, methyl, or amine, increases the relative efficacy by 2-9 fold. Extending the ethyl hydroxide tail of choline to propyl and butyl hydroxide also produces more efficacious agonists, by 4.8 and 25-fold, respectively. Perhaps the neuromuscular AChR has specifically evolved to be poorly activated by choline. Our findings reveal the amount of the energy available for AChR conformational change from different agonists. We are searching for the site(s) in the AChR that make choline such a low-efficacy agonist. Supported by NIH (NS-23513, NS-064969)." @default.
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- W2024170213 date "2011-02-01" @default.
- W2024170213 modified "2023-09-29" @default.
- W2024170213 title "Why is Choline Such a Low-Efficacy Agonist of the Neuromuscular Acetylcholine Receptor-Channel?" @default.
- W2024170213 doi "https://doi.org/10.1016/j.bpj.2010.12.2095" @default.
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