Identification of morphine-6-glucuronide in chromaffin cell secretory granules.
We report for the first time that morphine-6-glucuronide, a highly analgesic morphine-derived molecule, is present in adrenal chromaffin granules and secreted from chromaffin cells upon stimulation. We also demonstrate that phosphatidylethanolamine-binding protein (alternatively named Raf-1 kinase inhibitor protein or RKIP) acts as an endogenous morphine-6-glucuronide-binding protein. An UDP-glucuronosyltransferase 2B-like enzyme, described to transform morphine into morphine-6-glucuronide, has been immunodetected in the chromaffin granule matrix, and morphine-6-glucuronide de novo synthesis has been characterized, demonstrating the possible involvement of intragranular UDP-glucuronosyltransferase 2B-like enzyme in morphine-6-glucuronide metabolism. Once secreted into the circulation, morphine-6-glucuronide may mediate several systemic actions (e.g. on immune cells) based on its affinity for mu-opioid receptors. These activities could be facilitated by phosphatidylethanolamine-binding protein (PEBP), acting as a molecular shield and preventing morphine-6-glucuronide from rapid clearance. Taken together, our data represent an important observation on the role of morphine-6-glucuronide as a new endocrine factor.
Goumon
Yannick
Y
Physiopathologie du Système Nerveux, INSERM U575, 67084 Strasbourg, France. goumon@neurochem.u-strasbg.fr
Muller
Arnaud
A
Glattard
Elise
E
Marban
Céline
C
Gasnier
Claire
C
Strub
Jean-Marc
JM
Chasserot-Golaz
Sylvette
S
Rohr
Olivier
O
Stefano
George B
GB
Welters
Ingeborg D
ID
Van Dorsselaer
Alain
A
Schoentgen
Françoise
F
Aunis
Dominique
D
Metz-Boutigue
Marie-Hélène
MH
D000470:Alkaloids / Q000737:chemistry; D000727:Androgen-Binding Protein / Q000378:metabolism*; D000818:Animals; D015153:Blotting, Western; D002417:Cattle; D019439:Chromaffin Cells / Q000737:chemistry / Q000378:metabolism*; D002837:Chromaffin Granules / Q000378:metabolism; D002846:Chromatography, Affinity; D002851:Chromatography, High Pressure Liquid; D004587:Electrophoresis, Agar Gel; D004703:Endocrine System / Q000378:metabolism; D005089:Exocytosis; D014453:Glucuronosyltransferase / Q000378:metabolism; D006031:Glycosylation; D006801:Humans; D007150:Immunohistochemistry; D047468:Immunoprecipitation; D013058:Mass Spectrometry; D018613:Microscopy, Confocal; D008856:Microscopy, Fluorescence; D009020:Morphine / Q000494:pharmacology; D009022:Morphine Derivatives / Q000378:metabolism*; D049488:Phosphatidylethanolamine Binding Protein / Q000378:metabolism*; D022142:Secretory Vesicles / Q000378:metabolism*; D013347:Subcellular Fractions; D013997:Time Factors; D014357:Trypsin / Q000494:pharmacology; D014530:Uridine Diphosphate / Q000737:chemistry
D000470:Alkaloids; D000727:Androgen-Binding Protein; D009022:Morphine Derivatives; C511482:PEBP1 protein, human; D049488:Phosphatidylethanolamine Binding Protein; D014530:Uridine Diphosphate; C035349:morphine-6-glucuronide; D009020:Morphine; D014453:Glucuronosyltransferase; D014357:Trypsin