Ligand stabilization of CXCR4/delta-opioid receptor heterodimers reveals a mechanism for immune response regulation.
The CXCR4 chemokine receptor and the delta opioid receptor (DOR) are pertussis toxin-sensitive G protein-coupled receptors (GPCR). Both are widely distributed in brain tissues and immune cells, and have key roles in inflammation processes and in pain sensation on proximal nerve endings. We show that in immune cells expressing CXCR4 and DOR, simultaneous addition of their ligands CXCL12 and [D-Pen2, D-Pen5]enkephalin does not trigger receptor function. This treatment does not affect ligand binding or receptor expression, nor does it promote heterologous desensitization. Our data indicate that CXCR4 and DOR form heterodimeric complexes that are dynamically regulated by the ligands. This is compatible with a model in which GPCR oligomerization leads to suppression of signaling, promoting a dominant negative effect. Knockdown of CXCR4 and DOR signaling by heterodimerization might have repercussions on physiological and pathological processes such as inflammation, pain sensation and HIV-1 infection.
Pello
Oscar M
OM
Department of Immunology and Oncology, Centro Nacional de Biotecnología/CSIC, Madrid, Spain.
Martínez-Muñoz
Laura
L
Parrillas
Verónica
V
Serrano
Antonio
A
Rodríguez-Frade
José Miguel
JM
Toro
María José
MJ
Lucas
Pilar
P
Monterrubio
María
M
Martínez-A
Carlos
C
Mellado
Mario
M
D002448:Cell Adhesion / Q000502:physiology; D045744:Cell Line, Tumor; D002464:Cell Migration Inhibition / Q000502:physiology; D054377:Chemokine CXCL12 / Q000037:antagonists & inhibitors / Q000502:physiology; D019281:Dimerization; D020881:Enkephalin, D-Penicillamine (2,5)- / Q000378:metabolism; D006801:Humans; D019169:Jurkat Cells; D008024:Ligands; D019718:Receptors, CXCR4 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D017465:Receptors, Opioid, delta / Q000037:antagonists & inhibitors / Q000378:metabolism*
D054377:Chemokine CXCL12; C515256:Cxcl12 protein, mouse; D008024:Ligands; D019718:Receptors, CXCR4; D017465:Receptors, Opioid, delta; D020881:Enkephalin, D-Penicillamine (2,5)-