Morphine-like activity of natural human IgG autoantibodies is because of binding to the first and third extracellular loops of the mu-opioid receptor.
We have previously demonstrated that randomly selected healthy individuals express anti-human mu-opioid receptor antibodies which behave as agonist in vitro. In this study, we show that the activity of these antibodies was not affected by the deletion of the amino-terminal region of the receptor. Using agarose-bound peptide columns, we affinity-purified IgG specifically directed toward each extracellular loop. Whatever its specificity, each anti-human mu-opioid receptor (hMOR) extracellular loop peptide IgG preparation was unable, when examined individually, to reduce adenylate cyclase activity. Activation of the hMOR was, however, achieved by the simultaneous binding of IgG to the first and third extracellular loops of the receptor. Our results suggest that the simultaneous binding of IgG antibodies to these two loops mimics morphine-induced receptor activation by triggering a coordinated shift of the third and sixth transmembrane helices.
Macé
G
G
INSERM U28 and Université Paul Sabatier, IFR 30, Hôpital Purpan, Place du Dr Baylac, 31059 Toulouse Cedex, France.
Blanpied
C
C
Emorine
L J
LJ
Druet
P
P
Dietrich
G
G
D000595:Amino Acid Sequence; D000818:Animals; D001323:Autoantibodies / Q000276:immunology / Q000502:physiology*; D001665:Binding Sites; D016466:CHO Cells; D006224:Cricetinae; D004797:Enzyme-Linked Immunosorbent Assay; D006801:Humans; D007074:Immunoglobulin G / Q000276:immunology / Q000502:physiology*; D008969:Molecular Sequence Data; D009020:Morphine / Q000494:pharmacology*; D017450:Receptors, Opioid, mu / Q000737:chemistry / Q000276:immunology*
D001323:Autoantibodies; D007074:Immunoglobulin G; D017450:Receptors, Opioid, mu; D009020:Morphine