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Recent advances in Cys-loop receptor structure and function

Abstract

Throughout the nervous system, moment-to-moment communication relies on postsynaptic receptors to detect neurotransmitters and change the membrane potential. For the Cys-loop superfamily of receptors, recent structural data have catalysed a leap in our understanding of the three steps of chemical-to-electrical transduction: neurotransmitter binding, communication between the binding site and the barrier to ions, and opening and closing of the barrier. The emerging insights might be expected to explain how mutations of receptors cause neurological disease, but the opposite is generally true. Namely, analyses of disease-causing mutations have clarified receptor structure–function relationships as well as mechanisms governing the postsynaptic response.

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Figure 1: Structural model of the acetylcholine receptor from the Torpedo electric organ.
Figure 2: Mechanism of activation of acetylcholine receptors at the motor endplate.
Figure 3: Molecular dynamics simulation of AChBP showing mobility of loop C.
Figure 4: Principal pathway coupling acetylcholine binding to channel gating.
Figure 5: Energetic coupling of a charged residue pair that links agonist binding to channel gating.
Figure 6: Slow- and fast-channel phenotypes of congenital myasthenic syndrome.
Figure 7: CMS mutations occur in both binding and channel domains of the AChR.

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Acknowledgements

We thank H.-L. Wang and W. Y. Lee for generating the structural figures. Work in the authors' laboratories was supported by grants to S.M.S. and A.G.E. from the National Institutes of Health, and a grant to A.G.E. from the Muscular Dystrophy Association.

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Sine, S., Engel, A. Recent advances in Cys-loop receptor structure and function. Nature 440, 448–455 (2006). https://doi.org/10.1038/nature04708

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