1. Department of Neurobiology, The Hebrew University, Jerusalem, 91904, Israel
2. Department of Physiology, University of Wisconsin, Madison, Wisconsin 53706, USA
3. Department of Physiology and Pharmacology, Tel Aviv University, Tel-Aviv, 69978, Israel
4. Institute for Molecular Pediatric Sciences, University of Chicago, Chicago, Illinois 60637, USA
5. Present address: Neuroscience Department, The John Hopkins University Medical School, Baltimore, MD21205, USA

Correspondence to: Hanna Parnas¹ Correspondence and requests for materials should be addressed to H.P. (Email: hannap@huji.ac.il).

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 GPCRs^{2, 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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