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Biophys J
2016 Oct 04;1117:1396-1408. doi: 10.1016/j.bpj.2016.08.035.
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A Novel Voltage Sensor in the Orthosteric Binding Site of the M2 Muscarinic Receptor.
Barchad-Avitzur O
,
Priest MF
,
Dekel N
,
Bezanilla F
,
Parnas H
,
Ben-Chaim Y
.
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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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