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Institute of Pharmacology and Toxicology, University of Lausanne CH-1005 Lausanne, Switzerland
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONRESULTSDISCUSSIONMATERIALS AND METHODSREFERENCES |
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONRESULTSDISCUSSIONMATERIALS AND METHODSREFERENCES |
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-subunits
from their ß
-partners leads to activation of the intracellular
signaling pathways. Usually, after this first event, there is a rapid
desensitization of the receptors. This is observed by a decrease in the
maximum, and/or an increase in the EC50, of the
dose-response curve for production of intracellular second messengers
in a second exposure of the cells to the agonist. Also occurring with a
rapid kinetics is the internalization of the receptor-ligand complex by
endocytosis through coated pits. The molecular mechanisms underlying homologous and heterologous desensitization of these receptors usually involve phosphorylation of specific residues by different kinases. For instance, for the ß2-adrenergic receptor, heterologous desensitization can be induced by activation of protein kinase A (PKA) or protein kinase C (PKC), an effect that requires the presence of a PKA/PKC consensus site in the third intracellular loop of the receptor (1, 2, 3, 4). On the other hand, homologous desensitization results from receptor phosphorylation by G protein-coupled receptor-specific kinases (GRKs) (5), which form a family of structurally related isoforms (6). This phosphorylation takes place in the serine/threonine-rich C tail of the receptor (4) and induces association of the receptor with ß-arrestins (7, 8, 9, 10). This interaction prevents further activation of G proteins after agonist binding to the receptor and is thought to form the basis for the observed desensitization process.
Internalization of G protein-coupled receptors rapidly follows agonist binding and has initially been proposed to be involved in receptor desensitization (11, 12). More recently, studies have shown, on one hand, that desensitization could be suppressed by removing the GRK phosphorylation sites of the ß2-adrenergic receptor without impairing receptor internalization (4, 13). On the other hand, mutants unable to be internalized were still desensitized (14, 15). This indicated that internalization of the receptor-ligand complex and homologous desensitization were independent processes. This situation needs to be reappraised, however, in light of work demonstrating that internalization of the m2 muscarinic acetylcholine receptor can be facilitated by overexpression of GRK2 and that expression of a dominant negative mutant of this kinase decreases the rate of receptor internalization (16). Also, endocytosis of an internalization-resistant mutant of the ß2-adrenergic receptor could be induced by overexpression of GRK2, which phosphorylated the receptor (17). These two studies therefore suggest that phosphorylation by GRKs, if not totally required, may nevertheless participate in the endocytosis process. A role for ß-arrrestin in facilitating the internalization of GRK-phosphorylated ß2-adrenergic receptor has further been demonstrated (18), and ß-arrestin appears to function as a clathrin adaptor in receptor endocytosis (19). Together, the above evidence indicates that, although for some receptors desensitization and internalization are two events that can proceed independently of each other, phosphorylation of receptors by GRKs and consequent binding of ß-arrestins may participate in both phenomena.
Internalization of single transmembrane receptors such as those for
transferrin, low-density lipoproteins, insulin, and epidermal growth
factor require a tyrosine residue present in a tight-turn-forming motif
of the sequence NPXY (20, 21). Internalization of other membrane
proteins, such as the T lymphocyte CD3 antigen (22), the IgGFc receptor
(23), or the glucose transporter GLUT4 (24), depends in great part on
the presence of a dileucine internalization motif. For G-coupled
receptors, however, no specific internalization motif has been
described, although mutations of single amino acids may prevent
internalization in some instances. This is the case for tyrosine 326 of
the ß2-AR receptor (14), for three threonine residues of the
cytoplasmic tail of the m3 muscarinic acetylcholine receptor (25), and
for specific lysine residues of the yeast -pheromone receptor
(26).
The glucagon-like peptide-1 receptor is a G-coupled receptor expressed by pancreatic ß-cells (27). Binding of GLP-1 activates the adenylyl cyclase pathway, which ultimately results in the strong potentiation of glucose-induced insulin secretion (28, 29). We previously described that homologous and heterologous (PKC-induced) desensitization of the receptor strictly correlated with receptor phosphorylation in the last 33-amino acid segment of the receptor C tail (30). Furthermore, we showed that the PKC phosphorylation sites were four serine doublets present in this segment of the receptor and that serine doublet at position 431/432 was the major phosphorylation site (31). In this study we characterize the sites phosphorylated after agonist binding and demonstrate that these phosphorylation sites are required not only for homologous desensitization but also for internalization of the receptor-ligand complex.
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RESULTS |
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TOPABSTRACTINTRODUCTIONRESULTSDISCUSSIONMATERIALS AND METHODSREFERENCES |
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Here, to identify the phosphorylated amino acids, we first performed a
phosphoamino acid analysis of the phosphate-labeled receptor expressed
in fibroblasts or COS cells. Figure 1
shows that
phosphorylation of the GLP-1 receptor expressed in both cell types
occurs only on serine residues. To determine which serines were
phosphorylated in the carboxyl-terminal segment of the receptor, we
constructed several deletion and point mutants of the receptor. Figure 2 shows the sequence of the receptor cytoplasmic tail
and of the different mutants tested. Ten serines are present in the
region of the receptor that contains the phosphorylation sites and that
extends from serine 431 to the carboxyl end at position 463. Eight of
these serines are present as four doublets, and two individual serines
are at positions 461 and 463. In a first set of experiments,
carboxyl-tail deletion mutants were transiently expressed in COS cells.
Binding affinity and coupling to production of cAMP were identical for
the truncated mutants and the wild type receptor (not shown). After
radiolabeling with radioactive orthophosphate, the cells were exposed
to GLP-1 for 15 min and lysed, and the receptor was immunoprecipitated
and analyzed by gel electrophoresis. Figure 3A shows
phosphorylation of the wild type receptor and of deletion mutants
CT451 and CT444. No phosphorylation of the receptor, however,
could be detected in the CT441 and CT431 mutants. This suggests
that phosphorylation takes place at least on the last three serine
doublets but not on the doublet at position 431/2. Identical results
were obtained with the same truncation mutants stably transfected in
fibroblasts (Ref. 30 and not shown), therefore indicating no cell type
differences in receptor phosphorylation.
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shows that the mutants 451SS, 444SS, and 441SS were
phosphorylated after GLP-1 binding while mutant 431SS was not. These
data thus indicate that the last three serine doublets are
phosphorylated after agonist binding to its receptor. This is in
agreement with the results obtained with the deletion mutants.
Furthermore, because no phosphorylation can be detected in the 431SS
mutant, we conclude that serines at positions 461 and 463, which are
retained in this mutant, are not phosphorylated.
To determine whether phosphorylation was correlated with receptor
homologous desensitization, we established fibroblast cell lines
expressing the wild type or the different mutant receptors under the
control of the metallothionein promoter, as described (31). Figure 4 (left panel) shows that desensitization of
the wild type receptor could be measured by a decrease in the
Vmax for cAMP production by about 50%. In these cells only
a small shift in the EC50 for cAMP production was observed
(from 2 to 5.8 nM). Mutation of all three serine doublets
to alanine generated a receptor in which desensitization was almost
completely suppressed (Vmax = 
90% of nondesensitized
receptor) (Fig. 4, right panel). We similarly tested cell
lines expressing mutant receptors with only a single doublet or two
doublets mutated to alanine and evaluated the Vmax for cAMP
production after desensitization. Figures 5 and 7 show a
summary of the data obtained for all the clones tested. For the wild
type receptor, Vmax was reduced to 58% of the
nondesensitized receptor. With a single doublet mutated to alanine,
Vmax was reduced to 75–80% of nondesensitized receptor.
Double and triple mutants showed the same reduction of Vmax
after desensitization to 90% of the nondesensitized receptor. These
data indicate a correlation between the extent of phosphorylation and
the decrease in Vmax after desensitization. Phosphorylation
on at least two serine doublets is required to observe intermediate
desensitization, and maximal desensitization is only obtained when
phosphorylation occurs at all three identified sites.
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shows the acid wash-resistant
[125I]GLP-1 measured at 0 and 5 min. A nondissociable
component representing about 25% of initial binding is present at time
0 in all clones except in that expressing the 444/451AA mutant for
which this value, for an unknown reason, is 40%. The inset
in Fig. 6A shows the differences between the acid wash-resistant
[125I]GLP-1 at time 0 and 5 min, which represents the
peptide internalized over this period of time. Internalization is
maximal for the wild type receptor; it is reduced when any single
phosphorylation site is mutated to alanines; it is further decreased
when two sites are mutated and is suppressed in the absence of
phosphorylation sites (see Fig. 7). It appears, however,
that mutation of position 451/452 has a smaller effect in reducing
internalization than mutation of the two other sites. Also, mutation of
the three sites has a distinctly more pronounced effect on blocking
internalization as compared with the double mutant. These two features
indicate different correlation between phosphorylation and
internalization and phosphorylation and desensitization. Figure 6B
shows, by western blot analysis, the redistribution of the receptors to
light density vesicles (endosome-enriched) after exposure of the cells
to GLP-1. Whereas the wild type receptor content of light density
vesicles is increased and that of the heavy density vesicles (plasma
membrane-containing) is decreased upon exposure of the cells to GLP-1,
no such redistribution can be seen with the 431 SS mutant. This shows,
in an independent manner, that the suppression of the three
phosphorylation sites indeed prevents agonist-induced receptor
internalization.
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DISCUSSION |
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TOPABSTRACTINTRODUCTIONRESULTSDISCUSSIONMATERIALS AND METHODSREFERENCES |
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. Binding of GLP-1 to its receptor leads to activation of adenylyl cyclase and the production of cAMP. This signaling pathway can be attenuated by homologous desensitization but also after activation of PKC (heterologous desensitization). We previously showed that both forms of desensitization were additive in increasing the EC50 and decreasing the Vmax for cAMP production (30). Phosphorylation of the receptor induced by homologous and heterologous desensitization was also additive, suggesting that different amino acids were phosphorylated. PKC-induced desensitization of the receptor involved phosphorylation on the four serine doublets present in the last 32 amino acids of the receptor C tail (31). Here we provide evidence that the last three serine doublets of the C tail are the sites phosphorylated upon agonist binding. These sites thus overlap those phosphorylated by PKC activation. As these sites are doublets of serines, the additivity of the phosphorylation obtained in homologous and heterologous desensitization may be explained by phosphorylation on different serine residues at each of the doublets located at positions 441/442, 444/445, and 451/452 and by phosphorylation of doublet 431/432 uniquely by PKC. This is further supported by the fact that PKC induces only a marginal internalization of the receptor (30) compared with that induced by agonist binding, which requires receptor phosphorylation on the distal three sites. We have previously shown that neither PKC nor PKA were responsible for phosphorylation of the receptor after agonist binding (30). Receptor-specific kinases of the GRK family may thus be involved in this process. Studies in progress will indicate which, if any, of the so far identified GRKs participate in this phosphorylation process.
Implication of receptor phosphorylation in homologous desensitization
was studied after transfection of the wild type receptor or of mutants
thereof in fibroblasts using an expression vector containing the
metallothionein promoter. This promoter permits expression of the
receptor at a low level (2000–4000 receptors per cell), comparable to
the expression of the endogenous receptor in different insulinoma cell
lines (27). This is essential to perform desensitization experiments.
Indeed, in the presence of high surface expression, as obtained in COS
cells, the basal production of cAMP after a first stimulation of the
cells with GLP-1 is too high and does not permit generation of a
significant dose-response curve in a second exposure to the peptide.
With the presently used fibroblast cell lines, we could study the
effect of mutating the three phosphorylation sites together or in
different combinations. Our results indicated that desensitization
could be mostly, but not completely, suppressed by mutating the three
sites. This indicates that phosphorylation plays a major role in
inducing homologous desensitization but also suggests that additional
modifications may also participate in the observed desensitization.
These results are comparable to those obtained with the CT431
receptor (30), which is not phosphorylated but still partially
desensitized. Interestingly, however, we observed that the extent of
desensitization was dependent on the number of phosphorylation sites
present. When one site was removed, desensitization was intermediate,
and when two sites were mutated desensitization was as impaired as with
the triple mutant. Homologous desensitization is thought to be mediated
by ß-arrestin binding to phosphorylated receptors. Although the exact
mechanism for GLP-1 receptor desensitization is not known, our data
suggest that phosphorylation at multiple, adjacent sites is required to
generate high affinity binding sites for ß-arrestins.
Internalization of receptor-ligand complexes is an essential aspect of
the function of G protein-coupled receptors. It is required for
dissociation of the ligand from its receptor but also for
resensitization of the receptor (15, 33), probably by dephosphorylation
of the receptor by phosphatases encountered in the transit through the
endosomal compartment. Signals for internalization of this class of
receptors are not well defined. In the present study, we showed, using
point mutants, that removing the three phosphorylation sites led to a
complete suppression of receptor internalization. Mutation of one or
two sites, however, led to rates of internalization that were
intermediate between that of the wild type receptor and that of the
triple mutant. The different phosphorylation sites, however, appear to
contribute differentially to receptor endocytosis. This is especially
noticeable for the site at position 451/452, which has a significantly
smaller effect in reducing the internalization rate than mutation of
the other sites (see Fig. 7). Altogether, these data show that there is
thus a strict correlation between internalization and phosphorylation.
However, this correlation is qualitatively different from that observed
between phosphorylation and desensitization. This is evident especially
for the double and triple mutants. Whereas these two classes of mutants
are equally resistant to desensitization, there is a marked difference
in the ability of the double mutants to be internalized, at a reduced
but still significant rate, compared with the triple mutant, which is
not internalized at all. Also, mutation of site 451/452 has a much
lower effect in reducing internalization compared with mutation of
either of the two other phosphorylation sites. No such differential
effect on desensitization can be observed with the single mutants.
Together, these data indicate that phosphorylation of the receptor at
the identified sites by a kinase activated after agonist binding is
responsible for two events: homologous desensitization and receptor
internalization. The exact contribution of each phosphorylation site to
both mechanisms appears to be, at least in part, distinct, suggesting
that the molecular basis for the control of receptor desensitization
and endocytosis is different.
In pancreatic ß-cells, glucose-induced insulin secretion can be potentiated by activation of receptors linked to the adenylyl cyclase or the phospholipase C pathways. Activation of muscarinic receptors by carbachol strongly stimulates the insulin-secretory response but, at the same time, it induces a strong desensitization of the GLP-1 receptor (C. Widmann and B. Thorens, unpublished observations). By its poor ability to induce receptor internalization, PKC may desensitize the receptor for a longer period of time compared with homologous desensitization if internalization is primarily required for receptor resensitization. This may be of functional significance in the integration by ß-cells of different signals modulating insulin secretion, in particular in the postprandial state when cholinergic and gluco-incretin (GLP-1, glucose-dependent insulinotropic polypeptide) signals converge to the ß-cells to stimulate their secretory activity.
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MATERIALS AND METHODS |
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TOPABSTRACTINTRODUCTIONRESULTSDISCUSSIONMATERIALS AND METHODSREFERENCES |
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Mutagenesis
The different GLP-1 receptor mutants used in this study are
described in Fig. 2. The deletion mutant CT431 mutant was described
previously (30). The other mutations were generated by PCR
amplification, as described (31, 35), and each mutant was verified by
DNA sequencing. The mutant GLP-1 receptor cDNAs were subcloned in the
pcDNA-3 vector (Invitrogen, Leek, The Netherlands) and in the pmlMTIi
vector (30). The cDNAs subcloned in the pcDNA-3 and pmlMTIi vectors are
under the control of the cytomegalovirus and metallothionein promoters,
respectively.
Desensitization of the GLP-1-Induced cAMP Production
Desensitization was assessed as described earlier (30), by
comparing the dose-response curves of cAMP production as a function of
increasing GLP-1 concentrations for control cells and cells pretreated
for 15 min with 10 nM GLP-1 at 37 C.
Phosphorylation and Phosphoamino Acid Analysis
GLP-1-induced phosphorylation of the wild type or mutant GLP-1
receptors expressed transiently in COS cells was assessed as described
earlier (30). Briefly, COS cells were transiently transfected with the
different receptor cDNA constructs by the diethylaminoethyl-dextran
technique. For radiolabeling, cells were incubated for 2–3 h in the
presence of 500 µCi/ml of [32P]orthophosphate. GLP-1
(10 nM) was then added to the cells for 15 min, and the
cells were quickly washed in ice-cold PBS (8 g/liter NaCl, 0.2 g/liter
KCl, 1.44 g/liter Na2HPO4·2 H2O,
0.2 g/liter KH2PO4, pH 7.4). The cells were
detached from the culture dishes after a 10-min incubation with 1.5–2
ml of PBS, 1 mM EDTA and collected in an Eppendorf tube.
The cells were lysed in PBS containing 1% Triton X-100, 5
mM EDTA, 1 mM N-ethylmaleimide, 2
mM phenylmethylsulfonyl fluoride, 25 mM NaF,
and 1 mM NaVO4 for 10 min at 4 C.
Immunoprecipitation of the receptor and analysis by gel electrophoresis
were then performed exactly as described (31).
Phosphoamino acid analysis of the gel-purified receptor was performed by TLC using a HTLE 7000 electrophoresis system (C.B.S. Scientific Company, Del Mar, CA) according to the manufacturer’s protocol and Copper et al. (36).
Internalization of Receptor-Ligand Complex
Measurements of ligand-receptor internalization were performed
as previously described (32). Briefly, for evaluation of
[125I]GLP-1 endocytosis, the radiolabeled peptide (400
pM) was first bound at 4 C for 4–6 h, after which the
cells were washed with ice-cold HBSS containing 20 mM
HEPES, pH 7.4, and returned to 37 C for the indicated periods of time.
The cells were then washed with the HBSS buffer and lysed with 0.2
N NaOH/1% SDS, and the radioactivity was counted (total
binding). Alternatively, a duplicate set of cells was washed and
incubated for 2 min in an acidic solution (50 mM glycine,
150 mM NaCl, pH 3) to remove surface-bound radioactivity.
The cell-associated radioactivity that remained was considered to
represent the internalized peptide. A fraction of surface-bound
[125I]GLP-1 could not be removed at pH 3 before
incubation at 37 C (30%).
Analysis of GLP-1 receptor redistribution to endosomal compartments after GLP-1 binding was studied exactly as described (32). Briefly, cells expressing the wild type receptor or different mutants were exposed for 15 min to GLP-1 at 37 C. The cells were then treated with 500 µg/ml Concanavalin A and lysed in a hypotonic lysis buffer (1 mM Tris-HCl, pH 7.4, 2 mM EDTA). The cells were then scraped with a rubber policeman, and the total cell lysate was loaded on a discontinuous sucrose gradient consisting of 4 ml 60% sucrose, 4 ml 38% sucrose, and 4 ml 15% sucrose all made up in 20 mM Tris-HCl, pH 7.4. After centrifugation at 112,000 x g for 1 h at 2 C in a Beckman SW40 Ti rotor, the membrane fractions at the 25–38% sucrose interface (endosomal fraction) and 38–60% sucrose interface (plasma membrane fraction) were collected and analyzed for the presence of the receptor by Western blot analysis using receptor-specific antibodies (32).
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FOOTNOTES |
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B.T. was supported by a Career Development Award from the Swiss National Science Foundation. This work was supported by Grant 31–30313-90 from the Swiss National Science Foundation.
1 Present address: National Jewish Center for Immunology and Respiratory
Medicine, Pediatrics Department, 1400 Jackson Street, Denver, Colorado
80206. 
Received for publication January 14, 1997. Revision received March 11, 1997. Accepted for publication April 16, 1997.
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REFERENCES |
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TOPABSTRACTINTRODUCTIONRESULTSDISCUSSIONMATERIALS AND METHODSREFERENCES |
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