Role of electrostatic interaction in receptor-receptor heteromerization

Using pull-down and mass spectrometry experiments, we have previously demonstrated that adenosine A_2A-dopamine D₂ 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 (DD_401-402) or a phosphorylated Ser (pS₃₇₄) 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 D₁ receptor (L₃₈₇-L₄₁₆) and a specific region in the carboxyl terminus of the NR1-1 subunit of the NMDA receptor (E₈₃₄-S₉₃₈) are involved in D₁-NMDA receptor-receptor heteromerization. Careful perusal of these interacting regions shows the presence of a phosphorylated serine (pS₃₉₇) and adjacent glutamates (EE_404-405) in the D₁ receptor, whereas NR1-1 contains three adjacent Arg residues (RRR_893-896). 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-D₂ and D₁-NMDA, the epitope-epitope electrostatic interaction might represent an important general mechanism underlying receptor-receptor interactions.