title: A serine point mutation in the adenosine A2AR C-terminal tail reduces receptor heteromerization and allosteric modulation of the dopamine D2R.
abstract: Evidence exists that the adenosine receptor A(2A)R and the dopamine receptor D(2)R form constitutive heteromers in living cells. Mass spectrometry and pull-down data showed that an arginine-rich domain of the D(2)R third intracellular loop binds via electrostatic interactions to a specific motif of the A(2A)R C-terminal tail. It has been indicated that the phosphorylated serine 374 might represent an important residue in this motif. In the present study, it was found that a point mutation of serine 374 to alanine reduced the A(2A)R ability to interact with D(2)R. Also, this point mutation abolished the A(2A)R-mediated inhibition of both the D(2)R high affinity agonist binding and signaling. These results point to a key role of serine 374 in the A(2A)R-D(2)R interface. All together these results indicate that by targeting A(2A)R serine 374 it will be possible to allosterically modulate A(2A)R-D(2)R function, thus representing a new approach for therapeutically modulate D(2)R function.
authors.affiliation: Department of Neuroscience, Karolinska Institutet, Stockholm, Sweden. Dasiel.Borroto-Escuela@ki.se
authors.forename: Dasiel O
authors.initials: DO
authors.lastname: Borroto-Escuela
authors.forename: Daniel
authors.initials: D
authors.lastname: Marcellino
authors.forename: Manuel
authors.initials: M
authors.lastname: Narvaez
authors.forename: Marc
authors.initials: M
authors.lastname: Flajolet
authors.forename: Nathaniel
authors.initials: N
authors.lastname: Heintz
authors.forename: Luigi
authors.initials: L
authors.lastname: Agnati
authors.forename: Francisco
authors.initials: F
authors.lastname: Ciruela
authors.forename: Kjell
authors.initials: K
authors.lastname: Fuxe
mesh_terms: D000494:Allosteric Regulation; D002460:Cell Line; D006801:Humans; D017354:Point Mutation; D011487:Protein Conformation; D055503:Protein Multimerization; D043705:Receptor, Adenosine A2A / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D017448:Receptors, Dopamine D2 / Q000737:chemistry / Q000378:metabolism*; D012694:Serine / Q000235:genetics / Q000378:metabolism*
chemical_list: D043705:Receptor, Adenosine A2A; D017448:Receptors, Dopamine D2; D012694:Serine