title: Differential G-protein-coupled receptor phosphorylation provides evidence for a signaling bar code.
abstract: G-protein-coupled receptors are hyper-phosphorylated in a process that controls receptor coupling to downstream signaling pathways. The pattern of receptor phosphorylation has been proposed to generate a "bar code" that can be varied in a tissue-specific manner to direct physiologically relevant receptor signaling. If such a mechanism existed, receptors would be expected to be phosphorylated in a cell/tissue-specific manner. Using tryptic phosphopeptide maps, mass spectrometry, and phospho-specific antibodies, it was determined here that the prototypical G(q/11)-coupled M(3)-muscarinic receptor was indeed differentially phosphorylated in various cell and tissue types supporting a role for differential receptor phosphorylation in directing tissue-specific signaling. Furthermore, the phosphorylation profile of the M(3)-muscarinic receptor was also dependent on the stimulus. Full and partial agonists to the M(3)-muscarinic receptor were observed to direct phosphorylation preferentially to specific sites. This hitherto unappreciated property of ligands raises the possibility that one mechanism underlying ligand bias/functional selectivity, a process where ligands direct receptors to preferred signaling pathways, may be centered on the capacity of ligands to promote receptor phosphorylation at specific sites.
authors.affiliation: Department of Cell Physiology and Pharmacology, University of Leicester, Leicester, United Kingdom.
authors.forename: Adrian J
authors.initials: AJ
authors.lastname: Butcher
authors.forename: Rudi
authors.initials: R
authors.lastname: Prihandoko
authors.forename: Kok Choi
authors.initials: KC
authors.lastname: Kong
authors.forename: Phillip
authors.initials: P
authors.lastname: McWilliams
authors.forename: Jennifer M
authors.initials: JM
authors.lastname: Edwards
authors.forename: Andrew
authors.initials: A
authors.lastname: Bottrill
authors.forename: Sharad
authors.initials: S
authors.lastname: Mistry
authors.forename: Andrew B
authors.initials: AB
authors.lastname: Tobin
mesh_terms: D000818:Animals; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D043802:GTP-Binding Protein alpha Subunits, Gq-G11 / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D010766:Phosphorylation / Q000502:physiology; D043587:Receptor, Muscarinic M3 / Q000819:agonists / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology*
chemical_list: D043587:Receptor, Muscarinic M3; D043802:GTP-Binding Protein alpha Subunits, Gq-G11