title: The second intracellular loop of the m5 muscarinic receptor is the switch which enables G-protein coupling.
abstract: We have completed a systematic search of the intracellular loops of a muscarinic acetylcholine receptor for domains that govern G-protein coupling. A unique feature of the second intracellular (i2) loop was an ordered cluster of residues where diverse substitutions cause constitutive activation. A second group of residues in i2 was identified where mutations compromised receptor/G-protein coupling. The residues of each group alternate and are spaced three to four positions apart, suggesting an alpha-helical structure where these groups form opposing faces of the helix. We propose that the constitutively activating face normally constrains the receptor in the "off-state," while the other face couples G-proteins in the "on-state." Therefore, the i2 loop functions as the switch enabling G-protein activation.
authors.affiliation: ACADIA Pharmaceuticals Inc., San Diego, California 92121, USA.
authors.forename: E S
authors.initials: ES
authors.lastname: Burstein
authors.forename: T A
authors.initials: TA
authors.lastname: Spalding
authors.forename: M R
authors.initials: MR
authors.lastname: Brann
mesh_terms: D016475:3T3 Cells; D000595:Amino Acid Sequence; D019943:Amino Acid Substitution; D000818:Animals; D002460:Cell Line; D019204:GTP-Binding Proteins / Q000378:metabolism*; D015723:Gene Library; D006801:Humans; D007700:Kinetics; D051379:Mice; D008958:Models, Molecular; D008969:Molecular Sequence Data; D016297:Mutagenesis, Site-Directed; D017354:Point Mutation; D017510:Protein Folding; D017433:Protein Structure, Secondary; D043642:Receptor, Muscarinic M5; D011976:Receptors, Muscarinic / Q000737:chemistry* / Q000502:physiology*; D011994:Recombinant Proteins / Q000096:biosynthesis / Q000737:chemistry; D014162:Transfection
chemical_list: D043642:Receptor, Muscarinic M5; D011976:Receptors, Muscarinic; D011994:Recombinant Proteins; D019204:GTP-Binding Proteins