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The Structural Mechanism of the Cys-Loop Receptor Desensitization

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Abstract

The cys-loop receptors are neurotransmitter-operated ion channels, which mediate fast synaptic transmission for communication between neurons. However, prolonged exposure to the neurotransmitter drives the receptor to a desensitization state, which plays an important role in shaping synaptic transmission. Much progress has been made through more than half a century’s research since Katz and Thesleff first descried desensitization for muscle nicotinic acetylcholine receptor. In this review, we summarized recent research developments of receptor desensitization. Now, it has been identified that many parts of the receptor, such as the pore domain (including the hinge in the M2–M3 linker), the binding domain, the coupling region, and the intracellular domain, are all involved in the cys-loop receptor desensitization and that uncoupling between the amino-terminal domain and channel lining domain seems to play a central role in desensitization. This uncoupling is mainly governed by the balance between coupling strength and relative tightness of gating machinery and influenced by other parts of the receptor. Agonist binding induces conformational change to overcome the gating barrier to open the channel through the stressed coupling region, which is subsequently broken, causing receptor desensitization. With rapid advancement in structural biology of membrane receptors, final validation of this mechanism is expected to occur in the near future when the high-resolution structure of the desensitized state is available.

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Acknowledgments

This work was supported by grants from the National Natural Science Foundation of China (31100767, 31271136), Beijing Natural Science Foundation (KZ201210025020), and the National Basic Research Program of China (973 Program) (2012CB722407). We also thank Dr. Yongchang Chang from Barrow Neurological Institute, St. Joseph’s Hospital and Medical Center, (Phoenix, AZ, USA) for his help in proofreading the manuscript.

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The authors declare that they have no conflict of interest.

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  1. Beijing Institute of Brain Disorders, Capital Medical University, Key Laboratory for Neurodegenerative Disease of the Ministry of Education, Beijing Center of Neural Regeneration and Repair, Beijing Key Laboratory of Brain Major Disorders—State Key Lab Incubation Base, Beijing Neuroscience Disciplines, #10 Xitoutiao, Youanmenwai, Beijing, 100069, China

    Jianliang Zhang, Yujun Liu, Hui Yang & Xiaomin Wang

  2. Medical Experiment and Test Center, Capital Medical University, Beijing, 100069, China

    Fenqin Xue

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Zhang, J., Xue, F., Liu, Y. et al. The Structural Mechanism of the Cys-Loop Receptor Desensitization. Mol Neurobiol 48, 97–108 (2013). https://doi.org/10.1007/s12035-013-8420-z

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