G protein-coupled receptors (GPCRs) mediate many signal transduction processes in the body. The discovery that these receptors are voltage-sensitive has changed our understanding of their behavior. The M2 muscarinic acetylcholine receptor (M2R) was found to exhibit depolarization-induced charge movement-associated currents, implying that this prototypical GPCR possesses a voltage sensor. However, the typical domain that serves as a voltage sensor in voltage-gated channels is not present in GPCRs, making the search for the voltage sensor in the latter challenging. Here, we examine the M2R and describe a voltage sensor that is comprised of tyrosine residues. This voltage sensor is crucial for the voltage dependence of agonist binding to the receptor. The tyrosine-based voltage sensor discovered here constitutes a noncanonical by which membrane proteins may sense voltage.
Bibliographical noteFunding Information:
This work was supported by a grant from the National Institute for Psychobiology in Israel, founded by the Charles E. Smith Family, to Y.B.-C., by an internal research grant from the Open University in Israel to Y.B.-C., and by National Institutes of Health grant R01-GM030376 to F.B., with extra support to M.F.P. from F31-NS081954. O.B.-A. was supported by a fellowship from the Open University in Israel.
© 2016 Biophysical Society