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Introduction
G-protein-coupled receptor (GPCR) is the largest gene
family of human genome. GPCR is glaringly obvious by the
fact that more than 50% of drugs on the market are either
agonists or antagonists on GPCRs[1]. Positive or negative
modulation of GPCRs with drugs has been successful tools
to treat many diseases such as allergy, gastric ulcer, and
hypertension. The common structural feature of all GPCRs
is a seven-helical transmembrane region. GPCR activations
are evoked by stimuli as diverse as light,
Ca2+, odorants, amino acids, nucleotides, proteins, polypeptides, steroids,
and fatty acid derivatives.
The completion of the human genome project has
identified about 865 GPCR genes[2]. Except sensory receptors, 367
GPCRs have been considered as receptors for endogenous
ligands in the human genome[3]. However, identification of
novel members of GPCRs by genome sequencing faces
orphan receptor problem, that is, ligands are not yet
found[1]. About 150 orphan GPCRs are waiting for discovery of their
ligands[4]. Pairing orphan GPCRs with their own ligands
(endogenous or surrogate) would advance scientific
know-ledge and induces discovery of new
drugs[5-9]. However, recent double-pairing of OGR1 subfamily GPCRs with two
different chemicals, proton and lysolipid, raises several
questions.
First, whether both chemicals are the real ligands for OGR1
subfamily. Second, whether modulation of a GPCR by two
chemicals could be possible, because classic
pharmacological concept is one ligand for one GPCR. Third, one of the
chemicals is proton. Although it has been well established
for ion channel receptors such as transient receptor
potential/vanilloid receptor subtype-1
(TRPV1)[10] and acid-sensing ion channels
(ASICs)[11], in GPCR area, not only
proton-sensing is a new action mode of GPCR activation, but also it
could be generalized in other GPCRs.
OGR1 subfamily and lysolipids
OGR1 subfamily is composed of four members (OGR1,
GPR4, G2A, and TDAG8) and has previously been identified
as receptors for lysolipids; sphingosylphosphorylcholine
(SPC), lysophosphatidylcholine (LPC) and psychosine
(galactosylsphingosine)[12-14]. In 2000, Xu
et al reported Ovarian cancer G-protein-coupled Receptor 1(OGR1, GPR68)
to be a high-affinity receptor for SPC
(Kd = 33 nmol/L) and SPC was shown to inhibit cell growth of OGR1-transfected
HEK293 as well as various ovarian cancer cell
lines[12,15]. In 2001, Zhu et
al reported GPR4 to be the second high affinity
receptor for SPC and GPR4 was shown to be activated by structurally-related LPC[13]. However, in contrast to OGR1,
GPR4 activation stimulated cell growth and cell migration of
GPR4-transfected Swiss3T3 cells[13]. TDAG8 (T-cell
death-associated gene 8, GPR65) was reported to be activated by
psychosine and its activation was shown to result in
multinuclear cell formation[14]. G2A (G2 accumulation protein,
GPR132), the last member of the subfamily, was
characterized to cause cell cycle arrest in the
G2/M phase[16]. LPC was initially reported as a ligand of G2A and T cell chemotaxis to
LPC was shown to be mediated through
G2A[17].
Yan et al reported macrophage chemotaxis to LPC is
dependent on G2A function and mutation of the conserved
DRY motif of G2A results in loss of
function[18]. Wang et al demonstrated that murine G2A was spontaneously
internalized and accumulated in endosomal compartments, whereas
its surface expression was enhanced and stabilized by LPC
treatment[19]. Han et al reported G2A-mediated
up-regulation of CXCR4 in human helper T
cells[20]. Murakami et al reported G2A-dependent actin stress fiber formation and its
inhibition by LPC in G2A-NIH3T3
cells[21]. Also LPC enhances dose-dependently intracellular cAMP accumulation
and G2A-induced apoptosis in Hela
cells[22]. Ikeno et al reported that secretary phospholipase
A2 induce neurite outgrowth in PC12 cells through LPC generation and
activation of G2A receptor[23]. Lin and Ye reported that G2A
displays a significant level of intrinsic signaling via
Gaq, Gas, and
Ga13 pathways[22].
Lum et al showed that inflammatory stress increases GPR4
expression and LPC binding in human microvascular
endothelial cells[24]. Recently,
Kim et al reported that GPR4 plays a critial role in SPC-induced angiogenesis and SPC
trans-activates VEGF receptor 2 in endothelial
cells[25].
Maghazachi et al reported that psychosine and
glucosylsphingosine induce multinuclear cell formation and
apoptosis in TDAG8-expressing natural killer
cells[26]. Malone et al reported that activation of TDAG8 by
psycho-sine enhanced dexamethasone-induced apoptosis in a
TDAG8-dependent manner in lymphomas[27].
Tosa et al reported critical function of TDAG8 in glucocorticoid-induced
thymocyte apoptosis[28].
These ligand chemicals have similar lysolipid structures
(Figure 1) and their significance in pathological conditions
and pharmacological application has been discovered.
Especially, G2A deficient mouse developed an autoimmune
syndrome similar to systemic lupus erythematosus
(SLE)[29], and therapeutic application of LPC for sepsis was proposed
in relation with G2A receptor[30].
Overexpression of G2A, GPR4, and TDAG8 in human
cancers has been found to play a role in driving or maintain
ing tumor formation, however, transformation was achieved
without addition of lysolipids[31,32]. Bektas
et al reported ligand-independent signaling of GPR4 and its inability to
respond to SPC and LPC in several assay systems, that is,
GTPgS binding, receptor internalization, and arrestin
translocation[33]. Additionally, the original paper that reported
G2A-LPC pairing was recently retracted by authors, because
they could not confirm the LPC-binding
experiments[34]. Constitutive activation of GPCR and lipid-independent responses
raises a possibility, that is, another activator of GPCR is
present in the culture medium or secreted from
GPCR-transfected cells. Such a possibility has been suggested and
supported with proton by five independent
groups[21,35-38].
OGR1 subfamily as proton-sensing GPCRs
Ludwig et al (2003) reported OGR1 and GPR4 to be
proton-sensing receptors. At pH 7.8, OGR1 was inactive, but
activated fully inositol phosphate (IP) formation at pH 6.8.
Ludwig et al predicted several hydrogen-bond interactions
occurring between unprotonated histidines by using a
computational 3D model of OGR1. Under alkaline conditions
these interactions could stabilize the receptor in an inactive
state. Exposure to an acidic pH would destabilize the
hydrogen bonds, switching the receptor to its active conformation.
Indeed, mutation of several histidines (H17, H20, H84, H169,
and H269) to phenylalanines reduced proton-sensing ability
of OGR1 (Figure 2)[35]. In the same paper, authors observed
that a very similar activation of GPR4 by pH change, but
GPR4 activates the Gs-adenylyl cyclase-cAMP
pathway[35]. However, they were not able to observe any effect of SPC
and LPC, previously reported ligands, on OGR1 and GPR4.
In 2004, Murakami et al reported that G2A functions as a
proton-sensing GPCR[21]. Transient transfection of G2A
caused significant activation of the zif 268 promoter and IP
accumulation at pH 7.6 and lowering extracellular pH
augmented the activation only in G2A-expressing PC12h
cells[21]. Site-directed mutation of His-174, which is predicted to be
located at the extracellular part of the transmembrane helix IV
(Figure 2), reduced partially G2A-dependent signaling at
lower pH. They found that LPC and SPC did not cause IP
formation at pH 7.6, but LPC inhibited IP formation at pH 6.8
in a dose-dependent manner, suggesting that LPC acts as an
antagonist not an agonist. Wang et al
reported that TDAG8 is also a proton-sensing GPCR stimulating cAMP
accumulation[36]. They found that psychosine and SPC are
antagonistic on pH-dependent responses in the cells transfected with
TDAG8. Psychosine-sensitive and pH-dependent cAMP
accumulation was also observed in mouse thymocytes, where TDAG8 is endogenously expressed[36]. Radu
et al conducted experiments with all 4 members of OGR1 subfamily to test
proton-sensibility and confirmed previous reports on OGR1,
GPR4, and TDAG8[38]. However, G2A was insensitive or less
sensitive to extracellular pH change in their experimental
conditions[38]. They suggested that lack of many histidine
residues, defined to be involved in pH-sensing of OGR1,
could be a cause for insensitiveness of G2A to acidic pH
(Figure 2)[38]. Also they suggested that the constitutive
activation of G2A in neutral pH might be resulted from
maintaining active conformation of G2A via positively charged
amino acids in human and mouse G2A instead of conserved
histidines (Figure 2)[38]. Ishii et
al reported that TDAG8 is a proton-sensing GPCR, however, they were not able to
observe any inhibitory effect of psychosine on pH-dependent
TDAG8 activation[37]. Therefore, a series of publications
propose that extracellular proton could be an activator of the
OGR1 subfamily of GPCRs. More than two independent
groups reported proton-sensing properties of OGR1, GPR4,
and TDAG8 (Table 1). In the case of G2A, constitutive
activation at pH 7.4 has been observed in many transfected cells
by many research groups, however, pH-dependent
activation was supported only by one
group[21] and was not fully reproduced by another
group[38]. Dependence of pH sensing on the histidine residues on the extracellular domains of
GPCRs has been tested on OGR1, TDAG8, and
G2A[21,35-37]. However, site-directed mutagenesis study of the histidines
on GPR4 has not been experimentally reported.
In summary, there are four opinions in the published
reports, that is agonism of lysolipid, antagonism of lysolipid,
agonism of proton, and no confirmation of lysolipid action
on OGR1 subfamily GPCRs. Table 1 shows list of
publications supporting each opinion except negative observation
or constitutive activation.
Two ligands for a GPCR, proton vs lysolipid
As for lysolipids as ligands, Ludwig et al
could not confirm such activation of GPCRs with
lysolipids[35], and three research groups observed antagonistic effects of LPC, SPC
and psychosine on the GPCRs in acidic conditions rather
than agonism (Table 1)[21,36-38]. In summary, lysolipids have
been suggested as ligands for the OGR1 subfamily GPCRs,
however, all four members of the GPCRs have also
been proposed as proton-sensing GPCRs. OGR1 subfamily has been
considered as a contentious GPCR subgroup, because
pairing it with lysolipids has been controversial in the scientific
society[4,21,33,35,36]. Additionally, the original G2A paper was
retracted[34] and GPR4 paper would be retracted (Y XU,
FASEB conference, 2005). However, there are growing
numbers of reports supporting actions of lysolipids on OGR1
subfamily GPCRs (Table 1). As proposed by Kim et
al it can be dependent on cell types. Kim et al
recently confirmed pH-dependent cAMP production in GPR4-transfected
HEK293 cells but not in GPR4-transfected HUVEC or
HMEC-1 cells[25]. Cell-type specific functions remind us RAMPS
(receptor activity-modulating proteins) which are essential
proteins for expression and function of GPCRs such as CGRP
(calcitonin gene-related peptide) and
adrenomedullin[39]. If there are RAMP-like proteins specific for OGR1 subfamily,
the complicated results may be solved. Wang et
al recently observed spontaneous internalization of murine G2A and
reported that LPC induces surface redistribution and
stabilization of murine G2A[19]. Such an action of LPC may support
spontaneous activation of G2A and explain agonistic and
antagonistic effects of LPC. If spontaneous activity of G2A
was presumed as control level in neutral pH, LPC-induced
action might be interpreted as agonism. However, if
spontaneous activation or proton-activated effect was thought as
agonism, LPC-induced action might be considered as
antagonism. Further investigation on cell-type specificity
and receptor distribution in the cells may clarify action mode
of OGR1 subfamily GPCRs by both chemicals, proton and
lysolipids.
Therefore, it is not easy to say which chemical is the real
ligand, although both chemicals could be called as
modulators of the GPCRs. Finding of antagonistic effects of
lysolipids on the receptors at acidic conditions may advance
our understanding and might reconcile the controversy in
the future. If both chemicals could activate the same GPCRs
in certain conditions, another issue might be two ligands for
a GPCR. Dual actions may be a rare example in the GPCR
area. However, considering that TRPV1 could be activated
by capsaicin, proton, heat and lipids, two chemicals for a
GPCR could not be a surprising action mode in biological
sciences[10]. Investigation of physiological roles and
pathological implications of the GPCRs in the future may lighten
importance of discovery of proton-sensing GPCRs, because
acidosis is related with many diseases such as
cancer[40], asthma[41],
atherosclerosis[42],
arthritis[43], and
osteopenia[35,44].
Proton as an agonist
Another issue remains; could proton be a ligand? To be
an agonist, it should bind to GPCR specifically and
reversibly[45]. Furthermore, it should dose-dependently activate
GPCR. In five publications, proton has been shown to fulfill
all the above criteria, except specificity[21,35-38]
. Basal activity of many other GPCRs has been observed in neutral pH
without apparent presence of endogenous ligands as like
d-opioid receptor[46,47]. Such basal activity of GPCR has
further been confirmed by inverse agonists, which reduce the
basal activity in a dose-dependent
manner[46,47]. Many GPCRs have histidine residues in extracellular loops and outer
segments of GPCR helixes. Thus, if change of extracellular pH
could change basal activities of many GPCRs, although the
magnitude of change varies, this means lack of specificity. If
many GPCRs are activated or inactivated by change of pH
without presence of any agonists, proton can not be an
agonist, because it lacks specificity, even though OGR1
subfamily activation with proton was the greatest response
among GPCRs activated with proton. Indeed, modulation of
GPCRs by extracellular pH has been reported in
P2Y4 ATP receptor and calcium-sensing
receptor[48,49].
Four research groups have used the term
"proton-sensing GPCR" for OGR1 subfamily, however, the term for proton,
the counterpart, is omitted or the term "ligand" has been
used for proton. However, it is inadequate, because of the
above-mentioned reason, lack of specificity. GPCR
modulator may be the good term for proton, because it changes
activity of GPCRs, but it can not be an agonist. So far, the
smallest particle ever reported to be a GPCR activator is
photon. In this case, photon energy in light activates
rhodopsin GPCR by isomerisation of 11-cis-retinal to
trans conformation within the rhodopsin
helixes[50,51]. Now, proton might become the second small molecule activating
GPCRs. Although lysolipids as the ligand of OGR1
subfamily still remain controversial, proton as a ligand for the GPCRs
also need to be considered with caution, because an
endogenous ligand might be waiting to be discovered, suggesting
possible presence of another chemical to activate OGR1
subfamily in neutral conditions (Figure 3). It may not be a
surprise if there is another chemical activating OGR1 subfamily
in neutral pH such as prostaglandins and capsaicin
modulating TRPV1[52].
In summary, proton activates OGR1 subfamily GPCRs
and lysolipids modulate activity of OGR1 GPCRs positively
or negatively. However, we need to consider other two
possibilities. One is that modulation by proton could be
generalized in other GPCRs even though the magnitude
varies (Figure 3). Second, there could be another chemical
activating OGR1 subfamily in neutral pH (Figure 3).
Acknowledgement
The author thanks Prof Fumikazu OKAJIMA (Gunma University) for his critical comments.
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