MINIREVIEW
G Protein-coupled Receptors
III. NEW ROLES FOR RECEPTOR KINASES AND
-ARRESTINS IN
RECEPTOR SIGNALING AND DESENSITIZATION*
Robert J.
Lefkowitz
From the Departments of Medicine (Cardiology) and Biochemistry,
Howard Hughes Medical Institute, Duke University Medical Center,
Durham, North Carolina 27710
 |
INTRODUCTION |
Of the many forms of
GPCR1 regulation none has
received as much attention as the process of receptor desensitization,
i.e. the waning responsiveness of the receptors in the face
of persistent stimulation (1, 2). Numerous mechanisms have been
discovered, including those that operate at the transcriptional,
translational, and protein levels. The latter category in turn includes
mechanisms that regulate the rate of degradation of the receptors.
Finally, there are mechanisms for the covalent modification of the
receptors as well as for the regulation of their association with other proteins and their subcellular localization (1-3). This brief review
is concerned with this last group of mechanisms, which appears to be
most important with respect to the rapid (seconds-minutes as opposed
to hours or days) control of receptor function.
Traditionally, receptor desensitization has been viewed as a process
antithetical to receptor activation, one which terminates or attenuates
receptor signaling. Three families of regulatory molecules have been
found to participate in desensitization of heptahelical receptors:
second messenger-regulated kinases (e.g. PKA and PKC), GRKs
(e.g.
ARK, rhodopsin kinase), and the arrestins (visual
and non-visual). After briefly reviewing the well established paradigms
for regulation of GPCRs by these three families of molecules, I will
attempt to demonstrate how newly acquired insights into the function of
these receptor regulatory molecules are reshaping understanding of the
classical dichotomy between receptor activation and desensitization.
The new information suggests that receptor signaling and
desensitization are in reality two intimately linked aspects of
receptor function and that mechanisms previously viewed as
"desensitizing" with respect to one signaling pathway may be "activating" with respect to another.
 |
Established Paradigms |
Second Messenger Kinases--
One well established mechanism for
desensitizing GPCRs is via feedback regulation by the second
messenger-stimulated kinases, which they activate. Both PKA, activated
by Gs-coupled receptors, and PKC, activated by
Gq-coupled receptors, participate in such regulation (Refs.
1 and 4, and references therein). As first documented for the
2-adrenergic receptor, phosphorylation occurs on serine
residues located in the third cytoplasmic loop or C-terminal tail of
the receptors (5, 6). Phosphorylation directly alters receptor
conformation such that interaction with the G protein is impaired. This
type of receptor regulation generally mediates "heterologous" or
non-"agonist-specific" desensitization because any stimulant that
elevates cAMP (or diacylglycerol in the case of PKC) has the
potential to cause the phosphorylation and desensitization of any GPCR
containing an appropriate PKA and/or PKC consensus phosphorylation
site.
GRKs and
-Arrestins--
The major cellular mechanism mediating
rapid, agonist-specific, or homologous desensitization of G
protein-coupled receptors consists of a two-step process in which the
agonist-occupied receptors are phosphorylated by a GRK and then bind an
arrestin protein, which sterically interdicts signaling to the G
protein. These mechanisms have been extensively reviewed elsewhere (1,
2, 7-10). The family of GRKs currently includes six members (GRKs 1-6), of which the most thoroughly investigated are rhodopsin kinase
(GRK1) and
ARK1 (GRK2).
The arrestin family includes at least six members, several of which
undergo alternative splicing (2, 10). Some forms are found in the brain
and many other tissues (e.g.
-arrestins 1 and 2), whereas
others are confined to the retina (e.g. visual arrestins,
cone arrestin). Direct binding studies have demonstrated that
GRK-catalyzed phosphorylation of
2-adrenergic receptors increases affinity of
-arrestin binding 10-30-fold whereas agonist occupancy of the receptors has a much less significant effect on the
affinity of this interaction (11, 12). The regions on the arrestins
that bind to the intracellular loops of the receptors have been mapped
(13).
Regulation of GRKs--
An allosteric mechanism for activating
GRKs mediated by binding their substrates, the activated or
agonist-occupied receptors, has been explicitly demonstrated for both
GRK1 and -2 (14, 15). Other factors regulating activity include PKC
(16, 17), lipids (18, 19), and calcium-binding proteins such as
recoverin (20) and calmodulin (21, 22) (all reviewed in Ref. 7).
Several mechanisms for targeting GRKs to their membrane-bound receptor
substrates have been discovered. GRK2 and -3 appear to be largely
cytosolic enzymes. When an agonist stimulates a GPCR it causes the
receptor to interact with a heterotrimeric G protein leading to
dissociation into its
and 
dimer subunits (23). The 
subunit complex, which is prenylated with a geranylgeranyl group at the
C terminus of
(farnesyl in the case of transducin) is
membrane-bound (23). In a coordinated process, free G
and membrane phosphatidylinositol bisphosphate appear to bind to a C-terminal domain of GRK2 or -3, termed a pleckstrin homology domain
(19, 24). Interaction of these ligands with the pleckstrin homology
domain translocates or targets the kinase to the membrane-bound, agonist-occupied receptor, where it is then appropriately situated to
interact with its substrate. Different G
isoform combinations have preferential affinity for either GRK2 or -3, perhaps providing a
basis for specificity in GRK-receptor interactions (25). Distinct mechanisms appear to explain the membrane targeting of other members of
the GRK family (see Ref. 7).
GPCR Endocytosis--
Many GPCRs undergo agonist-promoted
endocytosis, internalization, or sequestration (3). Depending on the
receptor this may utilize the classical clathrin-coated vesicle
machinery or non-coated vesicle pathways (3). The functional
significance and mechanisms involved in GPCR sequestration have been
the subject of intense study and some controversy over the years.
Initially, it was thought that internalization of the receptors might
contribute to rapid desensitization. Later it was shown that rapid
functional uncoupling of the receptors did not require this process
(reviewed in Ref. 1). Subsequently, receptor sequestration was viewed as an early step in the so-called "down-regulation" of receptors, which occurs after prolonged (hours-days) agonist stimulation and
which ultimately ends in degradation within lysosomes. However, this
relationship remains unproven. Two other roles for receptor sequestration have recently received experimental support-receptor resensitization and receptor signaling. These are discussed below.
 |
New Paradigms |
Role of
-Arrestins and GRKs in Receptor
Endocytosis--
Several lines of evidence now indicate that
GRK-catalyzed phosphorylation of GPCRs followed by
-arrestin binding
are crucial steps in the internalization of several heptahelical
receptors (reviewed in Ref. 2). For example, in the case of the
m2-muscarinic cholinergic receptor, GRK2 overexpression enhances
sequestration, whereas a dominant negative form of
ARK1 retards it
in COS cells (26). Similar observations have been made with the
2-adrenergic receptor. In particular, a mutated
2-adrenergic receptor (Y326A), which is a poor substrate
for
-adrenergic receptor kinase, is not sequestered. Sequestration
of this receptor can be restored by overexpression of
ARK (27).
The role of GRK phosphorylation of the receptors in the sequestration
process is to facilitate
-arrestin binding. Thus,
-arrestin overexpression also restores sequestration of the
2-adrenergic receptor Y326A mutant and can promote the
sequestration of
2-adrenergic receptor mutants, which
lack the GRK phosphorylation sites (28). Further confirming the crucial
role of
-arrestins in the internalization process is the finding
that "dominant negative" forms of
-arrestin (e.g.
-arrestin1-V53D or S412D) strikingly impair receptor sequestration (28, 29). Supporting the generality of these mechanisms is the finding
that removal of the C-terminal tails (containing the likely sites of
GRK phosphorylation) from a number of different GPCRs impairs their
sequestration (2).
How does
-arrestin function to promote the internalization of GPCRs?
Recently it has been demonstrated, using purified proteins, that
-arrestins 1 and 2 (but not visual arrestin) bind directly, stoichiometrically, and with high affinity to clathrin (30).
-Arrestin/arrestin chimeras, which are defective in either
2-adrenergic receptor or clathrin binding, are impaired
in their ability to promote receptor endocytosis. Using
immunofluorescence microscopy of intact cells, agonist stimulation of
2-adrenergic receptors was shown to promote the
co-localization of the receptors and
-arrestin with clathrin. These
results suggest that
-arrestin functions in some way as an adaptor
in the clathrin-coated vesicle-mediated endocytosis of G
protein-coupled receptors (30). Whether, as it occurs in cells, this is
via a direct interaction with clathrin or with some other protein(s)
remains to be determined.
As noted above, however, not all GPCR endocytosis proceeds via
clathrin-coated vesicle pathways (2, 3). For example, internalization
of angiotensin II 1A receptors does not ordinarily utilize this pathway
as demonstrated by the lack of dependence of angiotensin II 1A receptor
sequestration on either
-arrestin or the GTPase dynamin (31).
However, when
-arrestin is overexpressed a fraction of the
angiotensin II 1A receptors can be made to engage the clathrin-mediated
pathway (31).
The function of
-arrestin 1 in GPCR sequestration is regulated by
phosphorylation/dephosphorylation of the
-arrestin molecule (29).
Cytoplasmic
-arrestin 1 is constitutively phosphorylated on Ser-412,
a C-terminal site. When it is recruited to the plasma membrane by
agonist stimulation of the
2-adrenergic receptors,
-arrestin 1 becomes rapidly dephosphorylated. This dephosphorylation is required for its function in the pathway of receptor endocytosis but
not for receptor binding and desensitization. Neither the kinase(s) nor
phosphatase(s) that participates in this regulatory process has as yet
been identified. This regulation of the endocytic function of
-arrestin 1 by dephosphorylation at the plasma membrane is
reminiscent of that previously demonstrated for the classical endocytic
adaptor protein complex AP2 (32). Interestingly, Ser-412 is not present
in other members of the arrestin family. Hence, the other arrestins
must be regulated by phosphorylation at other sites or by entirely
different mechanisms.
Receptor Endocytosis and Resensitization--
The process of rapid
agonist-induced desensitization is also generally rapidly reversible.
Thus after removal of the agonist isoproterenol from contact with
cells, adenylyl cyclase responsiveness to agonist generally returns to
normal within 15-30 min. As early as 1986, Sibley et al.
(33) suggested that
2-adrenergic receptor internalization played a role in receptor dephosphorylation and resensitization. It was observed that after agonist stimulation, receptors in internalized vesicles contained less phosphate than those
in plasma membrane fractions. Moreover, the vesicle fraction was
enriched in a phosphatase activity capable of dephosphorylating the
receptor. Later it was demonstrated that if
2-adrenergic receptor sequestration was blocked either by treatment of cells with
sucrose or by creating a sequestration-defective
2-adrenergic receptor mutant, the recovery from
desensitization normally observed within 20 min of removal of agonist
was blocked (34). The lectin concanavalin A, another reagent that
blocks receptor sequestration, also blocked resensitization (34), as do
dominant negative mutants of
-arrestin or dynamin, which inhibit
sequestration (35).
-Arrestin or GRK2 overexpression rescues
resensitization of a sequestration-impaired
2-adrenergic
receptor mutant (35).
The phosphatase responsible, at least for
2-adrenergic
receptor dephosphorylation, is a membrane-associated phosphatase of the
PP-2A family. It has been termed the GPCR phosphatase and, at least
in vitro, is active against not only the GRK-phosphorylated
2-adrenergic receptor but also the
2a-adrenergic receptor and rhodopsin (36). It is not
active against the PKA-phosphorylated
2-adrenergic
receptor. In vitro, the phosphatase is active on the
phosphorylated
2-adrenergic receptor only at acidic pH
(37). In intact cells, dephosphorylation of the receptors proceeds only after conformational changes in the receptor, which are apparently induced by the low pH uniquely present in the sequestered vesicles into
which they are internalized after agonist stimulation (Fig. 1). If the acidic pH normally found in
endosomal vesicles is disrupted by treatment of cells with
NH4Cl (37) or other reagents (38), receptor-phosphatase
association is blocked and receptor dephosphorylation does not occur.
Such treatments also block receptor resensitization (38). Taken
altogether these findings indicate that the very same molecules that
initiate receptor desensitization (
-arrestin and GRKs) also initiate
the process of internalization into acidified endosomal vesicles, which
is required for receptor dephosphorylation and resensitization. To date
the processes involved in receptor recycling to the plasma membrane
after dephosphorylation are not well understood.

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Fig. 1.
Multiple signaling roles of a GPCR
illustrated for the 2-adrenergic receptor. Agonist
occupancy of the receptor leads to activation of Gs and
adenylyl cyclase (signal 1). PKA phosphorylation of the receptor
uncouples it from Gs and facilitates its coupling to
Gi, which inhibits adenylyl cyclase (signal 2). GRK
phosphorylation of the receptor and subsequent -arrestin binding
further desensitize the receptor. -Arrestin also mediates
internalization of the receptor via clathrin-coated pits and vesicles.
Internalization of the receptors is required for activation of Erk1 and
-2 (signal 3) as well as for dephosphorylation and resensitization of
the receptors (see text for details). Other as yet unknown signals
might be generated as the receptor recycles to the plasma
membrane.
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Receptor Endocytosis and Mitogenic Signaling--
A wide variety
of GPCRs are able to activate MAP kinases such as Erk1 and -2 and in
some cases to thereby effect mitogenic responses (39, 40). The
mechanisms by which GPCR-mediated signals stimulate the Erks have been
extensively studied. Gi-, Gq-, and
Go-mediated pathways have been described (39). The Gi- mediated signals are generally carried by the G
subunits (39, 40), which lead to the activation of Src (or closely related tyrosine kinases) and subsequent tyrosine phosphorylation of
several adaptor (e.g. Shc) or "scaffold"
(e.g. epidermal growth factor receptor) proteins. This in
turn leads to the recruitment of the Ras nucleotide exchange complex
Grb2-mSOS to the plasma membrane. Sequential activation of Ras, Raf,
MEK, and the Erks follows (reviewed in Refs. 39 and 40, and references
therein).
Very recently, it has been discovered that activation of this pathway
by GPCRs requires their endocytosis (41, 42). Expression of dominant
negative mutants of
-arrestin or dynamin, which blocks receptor
endocytosis, blocks activation of MAP kinase (42). Other
mechanistically distinct inhibitors of clathrin-mediated endocytosis
such as concanavalin A, hypertonic sucrose, depletion of intracellular
potassium, low temperature, or monodansylcadaverine all have similar
effects (41). The site of the block has been localized to the
activation of MEK by Raf. Thus, in the presence of the endocytosis
inhibitors, GPCR-stimulated Shc tyrosine phosphorylation and Raf
activation proceed normally, yet Erk1 and -2 are not phosphorylated (42). The requirement for GPCR internalization for Erk1 and -2 activation is in striking contrast to well established paradigms for
classical plasma membrane-delimited, second messenger-generating signaling pathways, such as those involving adenylyl cyclase and phospholipase C. These pathways do not require GPCR endocytosis and are
unaffected by dominant negative forms of
-arrestin and dynamin
(42).
Because the requirement for GPCR endocytosis is relatively downstream
in the pathway leading to Erk1 and -2 activation why might
internalization of the receptor itself be required? One hypothesis is
that the agonist-occupied receptor organizes the assembly of a
multiprotein signaling complex at the plasma membrane including some or
all of the components in the pathway up to and including Raf.
Activation of MEK, however, presumably requires internalization of
active Raf, as part of a complex signaling particle stabilized in some
way by the receptor. Although such a mechanism is conjectural at this
point, what does seem clear is that GRK-catalyzed phosphorylation of
the receptor and subsequent
-arrestin-mediated internalization via
clathrin-coated pits are required for transduction of the MAP kinase
activation signal. Interestingly, recent evidence indicates that MAP
kinase activation by the tyrosine kinase epidermal growth factor
receptor also requires endocytosis of the receptor (43). This
represents an emerging analogy between GPCR-mediated and tyrosine
kinase receptor-mediated mitogenic signaling mechanisms (39). It should
be stressed that the involvement of GRKs and
-arrestins in
GPCR-mediated mitogenic signaling places these two "desensitizing"
proteins squarely in the role of important "signaling" molecules
(Fig. 1).
The cAMP-dependent Protein Kinase and Signal
Switching--
As described above, second messenger-activated kinases
such as PKA and PKC have been shown to desensitize GPCRs in a feedback regulatory fashion. Recent findings, however, suggest that this view
may be too limited and that in some cases "signal switching" rather
than signal desensitization may be a more appropriate description. It
has long been appreciated that many GPCRs can couple to multiple G
proteins, although often one pathway predominates over another. In the
case of the
2-adrenergic receptor, for example, most of its actions appear to be mediated by coupling to Gs and
activation of adenylyl cyclase. However, in some settings such as the
heart,
2-adrenergic receptors have been shown to
interact with Gi as well (44). What had not been
appreciated until quite recently, however, is the role of PKA-catalyzed
phosphorylation of the receptors in controlling the specificity of G
protein coupling.
When expressed in HEK 293 cells,
2-adrenergic receptors
activate Erk1 and -2 by the Gi
-mediated,
Ras-dependent pathway described above (45). The response is
blocked by pertussis toxin or reagents that sequester G
. However,
in contrast with the actions of more "classical"
Gi-coupled receptors such as that for lysophosphatidic
acid,
-adrenergic stimulation of the Erks is also blocked by the PKA
inhibitor H89 (45). Moreover, a mutated
2-adrenergic
receptor in which the two consensus PKA phosphorylation sites have been
removed fails to activate MAP kinase, although it is normal with
respect to mediating activation of adenylyl cyclase. In a direct assay
of receptor-G protein interaction, the ability of agonist-occupied
2-adrenergic receptors to catalyze GTP-GDP exchange on
Gi was blocked by H89. These findings indicate that in
order for the receptors to couple productively to Gi they must first interact with Gs, thereby inducing PKA
activation and phosphorylation of the receptors (45). The findings are
entirely consistent with earlier observations of Nishimoto and
co-workers (46). They found that a small peptide derived from the third cytoplasmic loop of the
2-adrenergic receptor (which
contains the PKA phosphorylation site) could directly activate
Gs but not Gi in vitro. When
phosphorylated by PKA, coupling to Gs was diminished and
that to Gi increased. Because coupling of
2-adrenergic receptors to Gi leads to
inhibition of adenylyl cyclase, this switching mechanism can be viewed
as yet another aspect of the overall desensitization process that is
engaged to blunt the Gs-mediated stimulation of adenylyl
cyclase. However, given the ability of Gi to couple the receptor to entirely distinct pathways (e.g. MAP kinase
activation), it is perhaps appropriate to frame this as a more general
mechanism for switching the coupling of receptors from one G protein to another (Fig. 1). Whether this mechanism also operates in PKC-mediated signaling pathways remains to be determined.
Novel Substrates for GRKs--
It has been thought that the only
substrates for GRKs are the GPCRs themselves. However, quite recently
it was discovered that tubulin is an excellent substrate as well (47).
In vitro, Km and
Vmax for tubulin phosphorylation by GRK2 are
essentially equivalent to the values obtained for the agonist-occupied
2-adrenergic receptor. In fact, GRK2 appears to account
for most of the endogenous "tubulin kinase" present in tissues. In
cells, stimulation of GPCRs leads to increased tubulin association with
GRK2 and increased tubulin phosphorylation. GRK2 can also be observed
to decorate cellular microtubules as assessed by immunofluorescence
microscopy (47). At present, the functional consequences of this
phosphorylation are unknown.
It seems likely that there may well be other non-receptor substrates
for GRKs. A provocative ramification of the existence of such
substrates relates to an interesting feature of the regulation of GRKs.
As noted above, it has been demonstrated for both GRK1 and GRK2 that
interaction of the GRK with its activated receptor substrate leads to
allosteric activation of the kinase (14, 15). Thus, once having bound
to a receptor, the kinase is activated as well with respect to other
substrates, e.g. tubulin. Although completely speculative at
present, these considerations raise the possibility that GRKs might
function directly as signaling elements representing essentially
agonist-activated kinases. The downstream components of such putative
signaling cascades remain to be determined.
Future Perspectives and Speculation--
To date the short list of
proteins shown to interact directly with GPCRs, in an
agonist-dependent fashion, includes heterotrimeric G
proteins,
-arrestins, and GRKs. One might speculate that the ability
of these proteins to interact with the receptors in a fashion directly
controlled by agonists situates them ideally to function as signaling
molecules. In the case of GRKs, as noted above, this simply requires
that there be non-receptor GRK substrates, such as tubulin. In the case
of
-arrestin, perhaps they function as adaptors linking the
agonist-occupied receptors to downstream signaling elements. The
recently discovered role of
-arrestins in receptor internalization
demonstrates how the
-arrestins can act as bifunctional molecules
linking the receptors to other cellular molecules. It will be
interesting to see what other such adaptor functions might be
identified for the
-arrestins.
Taken together, the information summarized here suggests that current
concepts of GPCR signaling and desensitization are continuing to
evolve. Molecules previously viewed as being exclusively involved in
receptor desensitization turn out to play crucial roles in receptor
signaling (Fig. 1). Increasingly, the various processes included under
the umbrella of "receptor desensitization" are revealed instead to
function as coordinated molecular switches turning on new signaling
pathways even as they turn off others.
 |
ACKNOWLEDGEMENTS |
I thank Julie Pitcher, Yehia Daaka, Louis
Luttrell, and Randy Hall for critical reading of the manuscript, Yehia
Daaka for help with preparation of the figure, and Donna Addison for
preparation of the manuscript.
 |
FOOTNOTES |
*
This minireview will be reprinted
in the 1998 Minireview Compendium, which
will be available in December, 1998. This is the third article of three in the "G
Protein-coupled Receptors Minireview Series."
To whom correspondence should be addressed: Depts. of Medicine
(Cardiology) and Biochemistry, Howard Hughes Medical Inst., Box 3821, Duke University Medical Center, Durham, NC 27710. Tel.: 919-684-2974;
Fax: 919-684-8875.
1
The abbreviations used are: GPCR, G
protein-coupled receptor; PKA, protein kinase A; PKC, protein kinase C;
ARK,
-adrenergic receptor kinase; GRK, G protein-coupled receptor
kinase; MAP kinase, mitogen-activated protein kinase; MEK, MAPK/ERK
kinase.
 |
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