of a number of cell types (Post and

Brown 1996). Theoretically, all pro-

Constitutively Signaling G-Protein- teins that comprise the signal trans-
duction pathways of GPCRs are po-
Coupled Receptors and Human tential targets for mutational events
Disease that can lead to constitutive (agonist-
independent) signaling and conse-
Leandros Arvanitakis, Elizabeth Geras-Raaka and quently disease. Indeed, mutations of a
number of G proteins have been shown
Marvin C. Gershengorn to cause disease in humans (Spiegel
1995). For example, mutations that
cause constitutive activation of the ␣
Dysregulation of G-protein-coupled receptor (GPCR) function has subunit of the stimulatory G protein,
been shown to be associated with a growing number of human dis- Gs, lead to increased cAMP formation
eases. In some diseases, mutation of an endogenous GPCR causes associated with pituitary tumors in
patients with acromegaly, hyperfunc-
the receptor to lose the ability to bind agonist or signal (‘loss of func-
tional thyroid nodules and the
tion’ mutation), whereas another mutation causes the receptor to be McCune–Albright syndrome. Simi-
in an active state in the absence of agonist (‘gain of function’ mu- larly, activating mutations of the ras
tation), leading to ‘constitutive signaling activity’. A number of consti- protein dysregulate the cell cycle and
tutively active GPCRs are tumorigenic in vitro and in animal models, are involved in the pathogenesis of
and cause syndromes of hyperfunction and/or tumors in humans. many human cancers. In this review,
we will limit our discussion to consti-
The recent characterization of a constitutively active GPCR in the
tutively active GPCRs and highlight
genome of a disease-associated, human herpesvirus provides a poten- those that have been found to be as-
tial novel mechanism for viral tumorigenesis. sociated with human disease.

The seven-transmembrane-helix, gua- H2N

nine nucleotide-binding (G) protein-
coupled receptors (GPCRs) (Figure 1)
represent the largest family of signal- Extracellular
transducing molecules known (Strader
et al. 1994). There are three subfamilies
of GPCRs: rhodopsin/␤2-adrenergic
receptors, calcitonin/parathyroid hor-
mone/parathyroid hormone-related
peptide receptors and metabotropic Transmembrane
glutamate/calcium-sensing receptors.
GPCRs convey signals for extracellu-
lar regulatory molecules as diverse
as hormones, neurotransmitters and
growth factors, as well as for calcium Intracellular
ions and photons. By coupling to G
proteins and activating effectors such HOOC
as adenylyl cyclase, ion channels or
phospholipase C that lead to in- Figure 1. Putative two-dimensional topology of a GPCR. GPCRs are integral membrane
creases (or decreases) in intracellular proteins with extracellular, transmembrane and intracellular domains. The extracellular
mediator molecules such as cAMP, amino terminus and three extracellular loops are at the upper part of the figure. The
seven ␣ helices that span the cell-surface membrane are in the middle of the figure. The
calcium ions or inositol 1,4,5-trisphos-
three intracellular loops and the intracellular carboxyl terminus are at the lower part of
phate and 1,2-diacylglycerol, GPCRs the figure. In three dimensions (not shown), the seven helices form a helical bundle that
regulate the activity of every cell in approximates a cylinder, with the seventh helix close to and interacting with the first and
the body. GPCRs regulate proliferation second helices.

Leandros Arvanitakis is at the Molecular Virology Laboratory, Hellenic Pasteur Institute, 127 Vas. Sofias Avenue, Athens GR-115 21, Greece;
Elizabeth Geras-Raaka and Marvin C. Gershengorn are at the Division of Molecular Medicine, Department of Medicine, Cornell University
Medical College, 1300 York Avenue, New York, NY 10021, USA.

TEM Vol. 9, No. 1, 1998 © 1998, Elsevier Science Ltd, 1043-2760/98/$19.00. PII: S1043-2760(98)00007-1 27
• GPCR Signaling
The changes in GPCR structure that
constitute receptor activation are not
known. It is thought that changes in
the conformation of the receptor, in
particular, changes involving the rela-
tive positions of the seven putative ␣
helices within the transmembrane
bundle, lead to changes in the intra-
cellular loops, causing increased affin-
ity for coupling to a heterotrimeric
G protein and thence to G-protein
activation. Activation of G proteins,
which are tethered to the inner surface
of the plasma membrane, is thought
to involve dissociation into two acti-
vated signaling molecules, namely,
the ␣ subunit bound to GTP and the
dimer of ␤␥ subunits, which are both
proximal mediators in signal trans-
duction cascades. In most cases with
native GPCRs, activation is initiated
by agonist binding. Larger agonists
bind primarily to the amino termini
and/or extracellular loops of GPCRs
and smaller ligands bind within the
GPCR transmembrane bundle. In
contrast, constitutively active GPCRs
achieve an active conformation with-
out agonist binding. Cells have counter-
regulatory mechanisms that attenuate
signaling by activated GPCRs. These
mechanisms include acute desensit-
ization involving GPCR-specific pro-
tein kinases and arrestins (homolo-
gous desensitization) and second
messenger-activated protein kinases,
such as protein kinases A and C
(heterologous desensitization). More
chronic decreases in GPCR sensitiv-
ity may be caused by decreases in re-
ceptor number (downregulation) that
may be caused by decreased GPCR
synthesis (decreased gene transcrip-
tion or increased messenger RNA
turnover) or enhanced GPCR degra-
dation secondary to increased recep-
tor internalization (by endocytosis
or sequestration) and degradation
within lysosomes. These counter-
regulatory mechanisms, however, do
not completely suppress constitutive
signaling (Lefkowitz et al. 1993).
• Native Mammalian GPCRs
A number of native mammalian
GPCRs have been shown to exhibit
28
constitutive signaling activity (Table
1). These include receptors from each
subfamily of GPCRs; for example,
␤2-adrenergic (Milano et al. 1994),
calcitonin (Cohen et al. 1997) and
metabotropic glutamate (Prézeau
et al. 1996) receptors. Moreover, in
some cases, for example mouse EP3
prostaglandin receptors (Hasegawa
et al. 1996), different isoforms pro-
duced by alternative RNA splicing
exhibit different levels of agonist-
independent signaling activity. In the
majority of cases, constitutive activ-
ity was shown with receptors studied
in in vitro systems. It has become
standard to show constitutive activity
by expressing GPCRs at various
levels (usually by transfection with
various amounts of plasmid encoding
cloned receptor complementary
DNAs) in cells in culture and demon-
strating that there is a direct relation-
ship between the level of GPCR ex-
pression and basal signaling. Human
␤2-adrenergic receptors were found
to be constitutively active by showing
that basal adenylyl cyclase activity in
membranes isolated from transfected
cells correlated directly with the level
of receptors (Samama et al. 1993)
and the basal level of cAMP in intact
cells (in the presence of cAMP phos-
phodiesterase inhibitors) was found
to correlate directly with the level of
rat histamine H2 receptors (Smit et
al. 1996). It is noteworthy that with
Table 1. Native mammalian GPCRs that exhibit constitutive activitya
Receptor
Human ␤2-adrenergic
Rat B2 bradykinin
Human calcitonin
Human CB1 cannabinoid
Rat D1B dopamine
Rat metabotropic glutamate
Rat histamine H2
Rat 5-hydroxytryptamine2C
Mouse melanocortin
Rat ␦-opioid
Mouse EP3 prostaglandin
Mouse thyrotropin-releasing hormone
aIf the same receptor from another species or another isoform of a listed receptor is constitutively active,
only one receptor is listed.
the use of these types of measure-
ments constitutive activity has been
more readily demonstrated with
GPCRs that couple to the adenylyl
cyclase–cAMP signal transduction
pathway than to the phospholipase
C–inositol 1,4,5-trisphosphate–1,2-
diacylglycerol cascade. Human calci-
tonin receptors, which couple to both
of these signal transduction path-
ways (Nussenzveig et al. 1994), were
shown to stimulate cyclic AMP for-
mation constitutively, but not inosi-
tol 1,4,5-trisphosphate formation
(Cohen et al. 1997). Indeed, agonist-
independent signaling activity of the
mouse thyrotropin-releasing hormone
receptor could not be demonstrated
by measuring second messenger for-
mation and relied on a sensitive re-
porter gene assay in which 1,2-diacyl-
glycerol activation of protein kinase
C leads to transcription of a firefly
luciferase reporter gene (Jinsi-Parimoo
and Gershengorn 1997). A clear
demonstration that constitutive sig-
naling by a native mammalian recep-
tor may lead to changes in cell
function in vivo has been provided
for human ␤2-adrenergic receptors
(Milano et al. 1994, Bond et al. 1995).
Transgenic mice overexpressing
human ␤2-adrenergic receptors only
in their hearts exhibited enhanced
myocardial function that was caused
by the agonist-independent activity
of these receptors.
Reference
Milano et al. (1994)
Leeb-Lundberg et al. (1994)
Cohen et al. (1997)
Bouaboula et al. (1997)
Tiberi and Caron (1994)
Prézeau et al. (1996)
Smit et al. (1996)
Barker et al. (1994)
Robbins et al. (1993)
Costa et al. (1992)
Hasegawa et al. (1996)
Jinsi-Parimoo and Gershengorn (1997)
TEM Vol. 9, No. 1, 1998
 An approach that is complemen-
tary to that described above to show
constitutive activity of receptors is
the use of ligands that exhibit inverse
agonism (or negative antagonism)
(Schutz and Freissmuth 1992). An
inverse agonist is a ligand that in-
hibits agonist-independent signaling
activity (Costa et al. 1992). Inhibition
of basal signaling by inverse agonists
provides evidence that the targeted
receptor is the specific cause of this
activity. Ligands that display inverse
agonism have been identified for
a number of GPCRs including ␤2-
adrenergic (Chidiac et al. 1994),
5-hydroxytryptamine2C (Labrecque
et al. 1995), opioid (Costa et al. 1992),
parathyroid hormone/parathyroid
hormone-related peptide (Gardella et al.
1996), B2 bradykinin (Leeb-Lundberg
et al. 1994) and thyrotropin-releasing
hormone (Heinflink et al. 1995) re-
ceptors; these ligands were used to
confirm the constitutive signaling
activity of these native receptors.
In conclusion, it is now evident
that a number of native mammalian
receptors exhibit constitutive signal-
ing activity. However, as these demon-
strations have been made primarily
in in vitro systems in which there
is marked overexpression of GPCRs,
the physiologic role of agonist-
independent signaling of native
GPCRs expressed at usual levels in
animals and humans is not clear.
• Endogenous GPCRs and Human
Disease
Most GPCRs that have been found to
be basally active are mutated recep-
tors in which mutations occurred
Table 2. Constitutively active GPCRs that cause disease in humans
Receptor
Calcium sensor
LH
PTH/PTHrP
Rhodopsin
Rhodopsin
TSH
TSH
LH, luteinizing hormone; PTH/PTHrP, parathyroid hormone/parathyroid hormone-related peptide; TSH, thyroid-stimulating hormone or thyrotropin.
TEM Vol. 9, No. 1, 1998
naturally or were constructed in the
laboratory. Because the initial few
constitutively active mutant GPCRs
were receptors with changes in the
putative third intracellular loop or
sixth transmembrane helix, it was
thought that these domains were es-
pecially important sites for activating
mutations. It is now clear, however,
that mutations which affect many do-
mains in GPCRs can lead to agonist-
independent activity. Several reviews
have summarized many of the mu-
tations constructed in the laboratory,
and these will not be considered
further here [see, for example (Scheer
and Cotecchia 1997)]. An important
consequence of the expanding aware-
ness of constitutive signaling activity
of GPCRs is the realization that a
number of human diseases are caused
by mutations in GPCRs that lead to
constitutive signaling (Table 2) (Spiegel
1995). Receptors from each subfamily
of GPCRs have been found to cause
human disease in this way. These
mutations may arise in cells in the
germline or in somatic cells and are
dominant. A mutation that allows
activation at lower calcium levels was
identified in the extracellular amino-
terminal domain of the calcium-sens-
ing receptor that leads to familial
hypoparathyroidism (autosomal domi-
nant hypocalcemia) (Chattopadhyay
et al. 1996). A mutation in the sixth
transmembrane helix of the receptor
for luteinizing hormone was the first
mutation found to cause familial male
precocious puberty (Shenker et al.
1993). A number of other activating
mutations of this receptor have been
found in other patients with this
Disease
Familial hypoparathyroidism
Familial male precocious puberty
Jansen metaphyseal chondroplasia
Congenital night blindness
Retinitis pigmentosa
Hyperfunctional thyroid nodules
Familial non-autoimmune hyperthyroidism
disorder (Kosugi et al. 1995). A
constitutively activating mutation in
the first transmembrane domain of
the receptor for parathyroid hor-
mone/parathyroid hormone-related
peptide has been described in a pa-
tient with Jansen-type metaphyseal
chondrodysplasia (Schipani et al.
1995). A mutation in the second
transmembrane domain of rhodopsin
leads to constitutive activation and
causes congenital night blindness
(Rao et al. 1994), whereas a mutation
in the seventh transmembrane do-
main of rhodopsin leads to persistent
activation of photoreceptor cells and
is the probable cause of retinal cell
degeneration in retinitis pigmentosa
(Robinson et al. 1992). The receptor
for thyroid-stimulating hormone
(TSH) has been found to be mutated
at several sites that lead to constitu-
tive activation (Van Sande et al.
1995). When activating mutations
of the TSH receptor occur in the
germline, they cause familial non-
autoimmune hyperthyroidism, in
which there is symmetric enlarge-
ment of the thyroid gland, whereas
somatic mutations lead to hyperfunc-
tioning (‘toxic’) thyroid adenomas
and the remainder of the thyroid
gland is unaffected. Thus, a number
of mutant GPCRs have been found to
be constitutively active and cause dis-
ease in humans. The large number of
receptors in the GPCR family, along
with the diversity of signals mediated
by its members, makes it likely that
additional examples of naturally oc-
curring activated GPCR mutants
of pathogenic significance will be
discovered.
Reference
Chattopadhyay et al. (1996)
Themmen et al. (1997)
Schipani et al. (1995)
Rao et al. (1994)
Robinson et al. (1992)
Van Sande et al. (1995)
Van Sande et al. (1995)
29
• Viral GPCRs and Disease
Throughout their evolution, viruses
have acquired host-cell genes that,
most likely, enhance their propa-
gation. Presumably, over time, natural
selection would favor those viruses
that have recruited and subverted
genes critical to their survival within
host cells. It is thought that viruses
propagate more readily in metaboli-
cally active cells and that activation of
cellular metabolism is a consequence
of viral infection. There are three
viruses known to encode homologs of
mammalian GPCRs. It is possible that
virally encoded GPCRs are expressed
in infected cells and enhance viral
survival/propagation by activating
cellular metabolism. Genes encoding
three GPCR homologs were found
in the genome of the human cyto-
megalovirus (Chee et al. 1990), a
human herpesvirus involved in mono-
nucleosis syndromes in normal hosts
and severe inflammatory disorders in
immunocompromised patients. One
of these genes, US28, was found to
encode a GPCR that is a functional
homolog of human C-C chemokine
receptors (Gao and Murphy 1994).
[Chemokines are peptides that cause
chemotaxis. Chemokines may be di-
vided into several classes, including
C-C chemokines (␤ chemokines), in
which two highly conserved Cys
residues at the peptide amino termini
are proximate to one another, and
C-X-C chemokines (␣ chemokines),
in which these two highly conserved
Cys residues are separated by any
amino acid.] The genome of Herpes-
virus saimiri, a T-lymphotropic
gammaherpesvirus which causes
lymphoproliferative disorders in sev-
eral non-human primates, contains a
gene, ECRF3, which encodes a GPCR
homolog (Nicholas et al. 1992) that is
a functional homolog of human C-X-C
receptors (Ahuja and Murphy 1993).
US28 and ECRF3 are activated by
certain C-C or C-X-C chemokines, re-
spectively, but do not exhibit consti-
tutive signaling activity. The role(s)
of US28 or ECRF3 in disease patho-
genesis is unclear.
Kaposi’s sarcoma-associated herpes-
virus (KSHV, human herpesvirus 8)
30
is a recently identified virus that
is strongly associated with all forms
of Kaposi’s sarcoma, primary effu-
sion lymphomas and multicentric
Castleman’s disease (Chang et al.
1994), and perhaps with multiple
myeloma (Rettig et al. 1997). KSHV
encodes a GPCR (ORF 74, KSHV-
GPCR) that is also homologous
to human chemokine receptors
(Cesarman et al. 1996). KSHV-GPCR
is expressed at the messenger RNA
level in tissues from patients with
Kaposi’s sarcoma and also in B-cell
lymphomas (Cesarman et al. 1996).
For GPCRs encoded within viral
genomes, KSHV-GPCR is novel in
that it exhibits constitutive signaling
activity (Arvanitakis et al. 1997).
KSHV-GPCR signals via the phospho-
lipase C–inositol 1,4,5-trisphosphate–
1,2-diacylglycerol pathway (Arvanitakis
et al. 1997) and activates the Jun
kinase/stress-activated protein kinase
and p38-mitogen-activated protein
kinase pathways (Bais et al. 1998).
KSHV-GPCR is also more promiscu-
ous than most chemokine receptors
in that it binds C-C and C-X-C chemo-
kines. Because constitutive activation
of the signaling pathways activated
by KSHV-GPCR induces cell prolifer-
ation and transformation (Post and
Brown 1996) and constitutively ac-
tive GPCRs cause tumors in humans
(see above), the potential role of
KSHV-GPCR in the pathogenesis of
the tumors associated with KSHV in-
fection was studied. We showed that
expression of KSHV-GPCR in rat
NRK fibroblasts stimulates cell pro-
liferation (Arvanitakis et al. 1997),
that KSHV-GPCR can transform
mouse NIH 3T3 fibroblasts in vitro
and that KSHV-GPCR-expressing
NIH 3T3 cells form tumors in mice
(Bais et al. 1998). Thus, KSHV-GPCR
displays activities of human onco-
genes. Moreover, we found that in
NIH 3T3 cells, KSHV-GPCR induces
the expression of vascular endo-
thelial growth factor, a potent and
efficacious stimulator of angiogen-
esis. This latter finding, which must
be shown in relevant cell types, is
noteworthy because exuberant angio-
genesis is characteristic of Kaposi’s
sarcoma lesions. Thus, because of its
tumorigenic and angiogenic poten-
tial, KSHV-GPCR is likely, along with
several other genes encoded by KSHV
(Russo et al. 1996), to play a role in
the pathogenesis of diseases associ-
ated with KSHV infection.
• Conclusions
It is now evident that a number of
native GPCRs exhibit constitutive sig-
naling activity but the role of agonist-
independent activity in normal physi-
ology is not known. On the other
hand, a number of constitutively ac-
tive GPCRs are involved in the patho-
genesis of human disease. Given the
large number of GPCRs encoded
within the human genome, estimated
to be more than 800, additional
examples of this pathogenetic mecha-
nism are likely to be uncovered.
Furthermore, the spectrum of dis-
eases caused by constitutively active
GPCRs is expanding to include dis-
eases caused by infectious agents. We
think that a more complete eluci-
dation of the roles of constitutively
active GPCRs (which may be pro-
duced by mutation of native GPCR
genes or by acquisition of novel
GPCR genes during infection) in
human disease and an understanding
at the molecular level of how these
pathogenic GPCRs could be inacti-
vated may allow rational develop-
ment of specific inverse agonists as
therapeutic agents.
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