title: A Novel Voltage Sensor in the Orthosteric Binding Site of the M2 Muscarinic Receptor.
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.
authors.affiliation: Department of Neurobiology, Institute of Life Sciences, The Hebrew University, Jerusalem, Israel.
authors.forename: Ofra
authors.initials: O
authors.lastname: Barchad-Avitzur
authors.affiliation: Department of Biochemistry and Molecular Biology, The University of Chicago, Chicago, Illinois.
authors.forename: Michael F
authors.initials: MF
authors.lastname: Priest
authors.affiliation: Department of Neurobiology, Institute of Life Sciences, The Hebrew University, Jerusalem, Israel.
authors.forename: Noa
authors.initials: N
authors.lastname: Dekel
authors.affiliation: Department of Biochemistry and Molecular Biology, The University of Chicago, Chicago, Illinois.
authors.forename: Francisco
authors.initials: F
authors.lastname: Bezanilla
authors.affiliation: Department of Neurobiology, Institute of Life Sciences, The Hebrew University, Jerusalem, Israel.
authors.forename: Hanna
authors.initials: H
authors.lastname: Parnas
authors.affiliation: Natural and Life Sciences, Open University of Israel, Raanana, Israel. Electronic address: yairbc@openu.ac.il.
authors.forename: Yair
authors.initials: Y
authors.lastname: Ben-Chaim
mesh_terms: D000818:Animals; D001665:Binding Sites; D002118:Calcium / Q000737:chemistry / Q000378:metabolism; D002713:Chlorine / Q000737:chemistry / Q000378:metabolism; D004560:Electricity; D007477:Ions / Q000737:chemistry / Q000378:metabolism; D008564:Membrane Potentials / Q000187:drug effects / Q000502:physiology*; D008958:Models, Molecular; D018721:Muscarinic Agonists / Q000737:chemistry / Q000494:pharmacology; D009154:Mutation; D009865:Oocytes / Q000737:chemistry / Q000187:drug effects / Q000502:physiology; D018408:Patch-Clamp Techniques; D010862:Pilocarpine / Q000737:chemistry / Q000494:pharmacology; D011487:Protein Conformation; D000072417:Protein Domains; D043585:Receptor, Muscarinic M2 / Q000819:agonists / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D014443:Tyrosine / Q000737:chemistry / Q000378:metabolism; D014981:Xenopus
chemical_list: D007477:Ions; D018721:Muscarinic Agonists; D043585:Receptor, Muscarinic M2; D010862:Pilocarpine; D014443:Tyrosine; D002713:Chlorine; D002118:Calcium