A serine point mutation in the adenosine A2AR C-terminal tail reduces receptor heteromerization and allosteric modulation of the dopamine D2R.

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. Copyright (c) 2010 Elsevier Inc. All rights reserved.