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J Biol Chem, Vol. 275, Issue 18, 13727-13736, May 5, 2000
From the Synthesis and maturation of G
protein-coupled receptors are complex events that require an intricate
combination of processes that include protein folding,
post-translational modifications, and transport through distinct
cellular compartments. Relatively little is known about the nature and
kinetics of specific steps involved in these processes. Here, the human
Export from the Endoplasmic Reticulum Represents the Limiting
Step in the Maturation and Cell Surface Expression of the Human
Opioid Receptor*
§,,,¶
Département de Biochimie,
Université de Montréal, Montréal, Quebec H3C 3J7,
Canada and the § AstraZeneca R & D Montréal, St.
Laurent, Quebec H4S 1Z9, Canada
opioid receptor expressed in human embryonic kidney 293S cells is
used as a model to delineate these steps and to establish the kinetics
of receptor synthesis, glycosylation, and transport. We found that the
receptor is synthesized as a core-glycosylated
Mr 45,000 precursor that is converted to the
fully mature Mr 55,000 receptor with a
half-time of about 120 min. In addition to trimming and processing of
two N-linked oligosaccharides, maturation involves addition
of O-glycans containing N-acetylgalactosamine, galactose,
and sialic acid. In contrast to N-glycosylation, which is
initiated co-translationally and is completed when the protein reaches
the trans-Golgi network, O-glycosylation was
found to occur only after the receptor exits from the endoplasmic
reticulum (ER) and was terminated as early as the
trans-Golgi cisternae. Once the carbohydrates are fully processed and the receptor reaches the trans-Golgi network,
it is transported to the cell surface in about 10 min. The exit from the ER was found to be the limiting step in overall processing of the
receptor. This indicates that early events in the folding of the
receptor are probably rate-limiting and that receptor folding intermediates are retained in the ER until they can adopt the correct
conformation. The overall low efficiency of receptor maturation, less
than 50% of the precursor being processed to the fully glycosylated protein, further suggests that only a fraction of the synthesized receptors attain properly folded conformation that allows exit from the
ER. This indicates that folding and ER export are key events in control
of receptor cell surface expression. Whether or not the low efficiency
of the ER export is a general feature among G protein-coupled receptors
remains to be investigated.
*
This work was supported by grants from the Medical Research
Council of Canada (to M. B.) and from the Ella and Georg Ehrnrooth Foundation, the Helsinki University Pharmacy, and the Oulu University Scholarship Foundation (to U. P.-R.).The costs of publication of this
article were defrayed in part by the
payment of page charges. The article
must therefore be hereby marked
"advertisement" in accordance with 18 U.S.C. Section
1734 solely to indicate this fact.
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