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

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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Figure 1: Gating currents in m2R-expressing oocytes.
Figure 2: Voltage dependences of gating currents of m1R and m2R, and of the agonist affinity of m2R.
Figure 3: Gating currents and dose–response curves of mutated m2R.

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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.

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Correspondence to Hanna Parnas.

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Ben-Chaim, Y., Chanda, B., Dascal, N. et al. Movement of ‘gating charge’ is coupled to ligand binding in a G-protein-coupled receptor. Nature 444, 106–109 (2006). https://doi.org/10.1038/nature05259

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