Role of electrostatic interaction in receptor-receptor heteromerization

Using pull-down and mass spectrometry experiments, we have previously demonstrated that adenosine A(2A)-dopamine D-2 receptor-receptor heteromerization depends on an electrostatic interaction between an Arg-rich epitope from the third intracellular loop of the D-2 receptor (217RRRRKR222) and two adjacent Asp residues (DD401-402) or a phosphorylated Ser (pS(374)) residue in the carboxyl terminus of the A(2A) receptor. It has been demonstrated recently that a specific region in the carboxyl terminus of the dopamine D, receptor (L-387-L-416) and a specific region in the carboxyl terminus of the NR1-1 subunit of the NMDA receptor (E-834-S-938) are involved in D-1-NMDA receptor-receptor heteromerization. Careful perusal of these interacting regions shows the presence of a phosphorylated serine (pS(397)) and adjacent glutamates (EE404-405) in the D-1 receptor, whereas NR1-1 contains three adjacent Arg residues (RRR893-896). These epitopes are highly conserved in all species, a sign that the epitopes are likely to be involved in a physiologically significant activity. If similar epitopes are found to be involved in the formation of receptor heteromers other than A(2A)-D-2 and D-1-NMDA, the epitope-epitope electrostatic interaction might represent an important general mechanism underlying receptor-receptor interactions.