Role of electrostatic interaction in receptor-receptor heteromerization.
Using pull-down and mass spectrometry experiments, we have previously demonstrated that adenosine A2A-dopamine D2 receptor-receptor heteromerization depends on an electrostatic interaction between an Arg-rich epitope from the third intracellular loop of the D2 receptor (217RRRRKR222) and two adjacent Asp residues (DD401-402) or a phosphorylated Ser (pS374) residue in the carboxyl terminus of the A2A 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 (EE404-405) in the D1 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 A2A-D2 and D1-NMDA, the epitope-epitope electrostatic interaction might represent an important general mechanism underlying receptor- receptor interactions.
Woods
Amina S
AS
National Institute on Drug Abuse, Intramural Research Program, National Institutes of Health, Department of Health and Human Services, Baltimore, MD 21224, USA. awoods@intra.nida.nih.gov
Ciruela
Francisco
F
Fuxe
Kjell
K
Agnati
Luigi F
LF
Lluis
Carmen
C
Franco
Rafael
R
Ferré
Sergi
S
D000595:Amino Acid Sequence; D001665:Binding Sites; D019281:Dimerization; D006801:Humans; D013058:Mass Spectrometry; D008969:Molecular Sequence Data; D010446:Peptide Fragments / Q000737:chemistry; D011487:Protein Conformation; D043705:Receptor, Adenosine A2A / Q000737:chemistry* / Q000378:metabolism*; D017448:Receptors, Dopamine D2 / Q000737:chemistry* / Q000378:metabolism*; D055672:Static Electricity
D010446:Peptide Fragments; D043705:Receptor, Adenosine A2A; D017448:Receptors, Dopamine D2