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Updated: Mar 14, 2026

Author Spotlight: Functional Site-Directed Fluorometry in Native Cells to Study Skeletal Muscle Excitability
Published on: June 2, 2023
A Novel Voltage Sensor in the Orthosteric Binding Site of the M2 Muscarinic Receptor
Ofra Barchad-Avitzur1, Michael F Priest2, Noa Dekel1
1Department of Neurobiology, Institute of Life Sciences, The Hebrew University, Jerusalem, Israel.
Abstract:
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.
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