Letter | Published:

Movement of ‘gating charge’ is coupled to ligand binding in a G-protein-coupled receptor

Nature volume 444, pages 106109 (02 November 2006) | Download Citation

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Abstract

Activation by agonist binding of G-protein-coupled receptors (GPCRs) controls most signal transduction processes1. Although these receptors span the cell membrane, they are not considered to be voltage sensitive. Recently it was shown that both the activity of GPCRs2,3,4,5 and their affinity towards agonists6 are regulated by membrane potential. However, it remains unclear whether GPCRs intrinsically respond to changes in membrane potential. Here we show that two prototypical GPCRs, the m2 and m1 muscarinic receptors (m2R and m1R), display charge-movement-associated currents analogous to ‘gating currents’ of voltage-gated channels. The gating charge–voltage relationship of m2R correlates well with the voltage dependence of the affinity of the receptor for acetylcholine. The loop that couples m2R and m1R to their G protein has a crucial function in coupling voltage sensing to agonist-binding affinity. Our data strongly indicate that GPCRs serve as sensors for both transmembrane potential and external chemical signals.

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Acknowledgements

We thank T. Kubo for providing us with the clones for the m2R/L3-m1 and m1R/L3-m2 constructs. This work was supported by a grant to J. Dudel, I.P. and H.P. from the Deutsche Forschungsgemeinschaft, and by NIH grants to N.D., B.C. and to F.B.

Author information

Author notes

    • Yair Ben-Chaim

    Present address: Neuroscience Department, The John Hopkins University Medical School, Baltimore, MD21205, USA

Affiliations

  1. Department of Neurobiology, The Hebrew University, Jerusalem, 91904, Israel

    • Yair Ben-Chaim
    • , Itzchak Parnas
    •  & Hanna Parnas
  2. Department of Physiology, University of Wisconsin, Madison, Wisconsin 53706, USA

    • Baron Chanda
  3. Department of Physiology and Pharmacology, Tel Aviv University, Tel-Aviv, 69978, Israel

    • Nathan Dascal
  4. Institute for Molecular Pediatric Sciences, University of Chicago, Chicago, Illinois 60637, USA

    • Francisco Bezanilla

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Reprints and permissions information is available at www.nature.com/reprints. The authors declare no competing financial interests.

Corresponding author

Correspondence to Hanna Parnas.

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    Supplementary Notes

    This file contains Supplementary Figures 1–8, Supplementary Methods and additional references.

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https://doi.org/10.1038/nature05259

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