A Novel Voltage Sensor in the Orthosteric Binding Site of the M2 Muscarinic Receptor.
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.
Biophysical journal