Neural Effects of Lysophosphatidic Acid (LPA) SignalingNOBUYUKI FUKUSHIMA
18.1. INTRODUCTION
18.1.1. History of LPA Research in the Nervous System
Lysophosphatidic acid (LPA) is now widely recognized as an intercellular signaling lipid that produces or regulates many physiological functions in various organs. Looking back over the history of LPA research, there have been two breakthrough findings: the implication of the G protein-coupled LPA receptor in mediating LPA-induced cell proliferation in fibroblasts in 1989, and the identification of the first LPA receptor gene (Lpar1) in the mouse developing cerebral cortex in 1996 (1, 2). In addition, many LPA-induced cellular responses in neural cells have been observed in vitro and in vivo, the underlying molecular mechanisms of which have been closely exam-ined (3–7).
After Lpar1 was cloned, five additional LPA receptor genes were sequen-tially identified in mammals and found to consist of two distinct groups: the edg (endothelial differentiation gene) and non-edg families (7–9). The mouse edg family includes Lpar1, Lpar2, and Lpar3, and the non-edg family includes Lpar4, Lpar5, and Lpar6, which have been classified as orphan G protein-coupled receptors belonging to the purinergic receptor family. The identifica-tion of each LPA receptor gene has led to the finding that LPA receptors can couple to at least four distinct G proteins, Gi, Gq, G12/13, and Gs, and elicit various cellular responses depending on activated signaling pathways and cell types (5–8).
In conjunction with the investigation of LPA receptor functions, several LPA-producing enzymes have been identified, such as autotaxin (ATX)/
lysophospholipase D (encoded by ectonucleotide pyrophosphatase-phosphodiesterase 2 [Enpp2] gene) and membrane-bound phosphatidic acid-preferring phospholipase A1 (mPA-PLA1, encoded by lipase member H [Liph] gene) (10, 11). Investigators also discovered several LPA-hydrolyzing enzymes that terminate LPA-induced effects, such as lipid phosphate phos-phatases (LPPs) and plasticity-related gene-1 (PRG-1) (12, 13). Combined with the actions of LPA on neural cells, the expression profiles of LPA receptor genes and metabolizing enzyme genes in the nervous system have suggested that LPA signaling plays crucial roles in neural functions, both during develop-ment and in adulthood. This hypothesis has been further strongly supported by the generation and analyses of mice genetically engineered for LPA recep-tors, ATX, LPPs, or PRG-1, which have demonstrated that LPA receptor-mediated effects in neural cells are fundamental to proper nervous system development and neural function, and that abnormal LPA signaling may be linked with some neural diseases (Table 18.1) (7, 10, 14–16). In addition, the development and use of various chemical compounds acting on LPA receptors or ATX have also clarified the physiological significance of LPA signaling in the nervous system (7, 10, 15). This review discusses recent advances in the study of LPA receptor-mediated signaling in neural cells and its possible roles in neural development and diseases.
18.2. LPA SIGNALING IN NEURAL DEVELOPMENT
18.2.1. Neural Tube Formation
Neural tube formation is a very early event in nervous system development, accompanied by dynamic movement and shape changes of neuroepithelial cells in neural plates. Because LPA was shown to change cell shapes by induc-ing actin reorganization, the involvement of LPA receptor-mediated signaling in neural tube formation was anticipated. This hypothesis was also supported by in situ hybridization studies demonstrating that Lpar1, Lpar2, Lpar4, and Lpar5 were expressed in neural folds or tube during the early stage of embry-onic development (17). However, no defect in neural tube formation was observed in Lpar1-, Lpar2-, Lpar3-, or Lpar4-null mice or Lpar1/Lpar2/Lpar3-triple-null mice (18–22). In contrast to these mice, Enpp2-null mice showed the most striking defect in neural tube formation: the failure of neural tube closure (23–25). Thus, ATX-mediated LPA production may cooperate with LPA5 or a combination of several LPA receptor subtypes expressed during neural tube development.
Abnormal neural tube formation was also demonstrated in mice lacking LPP-3, encoded by the phosphatidic acid phosphatase 2b (Ppap2b) gene. These Ppap2b-null mice exhibited defects in vasculogenesis and axis patterning as early embryos, along with neural tube duplication, but not the closure deficit (26). By contrast, chicken β-actin promoter-driven Ppap2a (encoding LPP-1)
TAB
LE
18.
1. N
euro
nal P
heno
type
s O
bser
ved
in m
ice
Lac
king
gen
es f
or L
PA
Sig
nal-
Rel
ated
Mol
ecul
es
Targ
eted
Gen
eG
enot
ype
Phe
noty
peR
efer
ence
Lpa
r1H
omoz
ygou
sD
ecre
ased
neu
roge
nesi
s in
the
cer
ebra
l cor
tex
and
hipp
ocam
pus
19, 2
9, 4
9, 5
3, 7
9–82
, 89,
111
Anx
iety
-lik
e be
havi
orIm
pair
ed s
pati
al m
emor
yR
educ
ed n
euro
tran
smit
ter
rele
ase
Dec
reas
ed n
umbe
r of
inhi
bito
ry n
euro
ns in
the
ent
orhi
nal c
orte
xL
ack
of n
euro
path
ic p
ain
and
dem
yelin
atio
nIn
crea
sed
Schw
ann
cell
apop
tosi
s in
the
sci
atic
ner
veA
ggra
vati
on o
f ch
roni
c st
ress
-ind
uced
spa
tial
mem
ory
Lac
k of
hyp
oxia
-ind
uced
cor
tica
l dis
orga
niza
tion
Att
enua
tion
of
coca
ine-
indu
ced
cond
itio
nal l
ocom
otio
nL
par2
Hom
ozyg
ous
Inhi
biti
on o
f hy
pere
xcit
atio
n in
PR
G-1
hom
ozyg
ous
mic
e92
Lpa
r3H
omoz
ygou
sN
o ob
viou
s ph
enot
ype
repo
rted
18L
par4
Hom
ozyg
ous
No
obvi
ous
phen
otyp
e re
port
ed, o
r no
t fu
lly a
naly
zed
due
to
embr
yoni
c le
thal
ity
in a
sub
set
of h
omoz
ygou
s m
ice
21, 2
2
Enp
p2H
omoz
ygou
sD
efec
t in
neu
ral t
ube
clos
ure
23–2
5H
eter
ozyg
ous
Red
uced
neu
ropa
thic
pai
n11
3, 1
28, 1
29L
iph
Hom
ozyg
ous
No
obvi
ous
phen
otyp
e re
port
ed13
0P
pap2
aTr
ansg
enic
No
obvi
ous
phen
otyp
e re
port
ed28
Ppa
p2b
Hom
ozyg
ous
Neu
ral t
ube
dupl
icat
ion
26P
pap2
cH
omoz
ygou
sN
o ob
viou
s ph
enot
ype
repo
rted
27P
RG
-1H
omoz
ygou
sE
pile
ptic
sei
zure
92
401
402 NEURAL EFFECTS OF LPA SIGNALING
transgenic mice and Ppap2c (encoding LPP-2)-null mice showed no obvious phenotype in the nervous system (27, 28). LPPs metabolize not only LPA, but also other phospholipids, including phosphatidic acid and sphingosine 1-phosphate (12, 13). Thus, complicated phospholipid metabolism may be necessary for neural tube formation.
A recent study has shown that LPA1-mediated signaling contributed to initiation of fetal hydrocephalus, characterized by the abnormal accumulation and enlarged head (29). This severe neurological disorder may be develop-mentally related with neural tube defect, because patients with spina bifida or myelomeningocele often develop hydrocephalus (30, 31). Further studies to reveal the role of LPA signaling in early neural development should lead to the finding of new therapeutic treatment for fetal hydrocephalus.
18.2.2. Neurogenesis/Neuronal Differentiation
The Lpar1 gene was identified as the first LPA receptor gene and originally called ventricular zone gene-1 (vzg-1) due to its enriched expression in the ventricular zone (VZ) of the developing cerebral cortex (2). The VZ is the source of neuroblasts or neural cell progenitors, which differentiate into neurons or glial cells under spatiotemporal regulation. Expression analyses for other LPA receptor genes revealed that mouse embryonic brain tissue consisting of mostly neuroblasts or cortical neuroblast preparations highly expressed not only Lpar1, but also Lpar2 and Lpar4 (32–34). Functional studies demonstrated that exposure of neuroblast clusters to LPA induced morphological changes in vitro that were not observed in neuroblasts prepared from Lpar1-null mice (19, 35). Cortical neuroblasts also responded to LPA with electrically determined changes in ionic conductance, as well as Ca2+ mobilization determined by Ca2+ imaging analysis (32, 36). The Ca2+ responses were mediated primarily by LPA1, LPA2, and a combination of LPA1 and LPA2 receptors. Because intracellular Ca2+ concentrations play an important role in neuronal differentiation and proliferation (37–39), LPA receptor-mediated Ca2+ signaling may regulate cortical neurogenesis and differentiation during development.
Consistent with the findings mentioned above, an ex vivo culture system using the embryonic whole brain revealed that LPA signaling stimulated ter-minal mitosis of neuroblasts in the VZ, leading to neuronal differentiation (40). The LPA-induced stimulation of neuronal differentiation resulted in increased brain size, which led to the folding of cerebral cortex. This effect of LPA was not observed in brains derived from Lpar1/Lpar2-double-null mice. Stimulation of neuronal differentiation by LPA was also observed in an embryonic cerebral cortex-derived neurosphere culture supplemented with fibroblast growth factor (FGF) (41), which involved the differentiation of neuroblasts into neurons and oligodendrocytes, but not astrocytes. LPA stimu-lated neuronal differentiation and suppressed oligodendrocyte generation in
LPA SIGNALING IN NEURAL DEvELOPMENT 403
this culture system, and these effects were blocked when neurospheres were treated with an LPA1 antagonist or prepared from Lpar1-null mice (41). In this culture system, LPA alone failed to enhance neuroblast self-proliferation leading to the formation of neurospheres. By contrast, LPA was shown to generate neurospheres, consisting of Sca-1- and AC133-positive cells, from postnatal mouse brains in the absence of epidermal growth factor and FGF, possibly through LPA1 and/or LPA3 receptors (42). In a neurodifferentiation model using human embryonic stem cells, LPA inhibited differentiation without altering the proliferation and apoptosis of progenitor cells or astro-cytic differentiation (43, 44). Together, these findings suggest that LPA may regulate neuronal and glial differentiation in a developmental stage- or pro-genitor cell type-specific manner.
Proper cortical neurogenesis during embryonic development is essential for organized brain formation. Hypoxic insults during the neurogenic period could cause a range of neurological and psychiatric disorders, associated with cortical disorganization. Recently, LPA1 signaling has been demonstrated to be required for hypoxia-induced cerebral cortical disruption, including dis-placement of neuroblasts and impaired neuronal migration (45). This study further indicated that hypoxia resulted in overactivation of LPA1. Thus, these findings may propose new preventive or therapeutic treatment for hypoxia-related disorders.
Neuronal differentiation is also known to be directly and indirectly regu-lated by astrocytes. Cocultures of cortical neuroblasts with LPA-primed astro-cytes were shown to enhance neuronal differentiation and axon outgrowth (46, 47). This effect was reproduced when the conditioned medium of LPA-treated astrocytes was added to neuroblasts. Furthermore, the priming effects were lost in Lpar1/Lpar2-double-null astrocytes. Thus, LPA receptor-mediated sig-naling in astrocytes may also be involved in the indirect regulation of neuronal differentiation.
Despite in vitro evidence showing that LPA signaling may at least in part be involved in neuronal differentiation, as mentioned above, no obvious phenotype related to neurogenesis or neuronal differentiation was detected in the brains of Lpar1-, Lpar2-, or Lpar1/Lpar2-null mice (19, 20). This observation suggested some unidentified redundancies, because other LPA or related lysolipid recep-tors, including sphingosine 1-phosphate receptors, were found to be expressed in developing cerebral cortex (17, 48). An alternative possibility is differing genetic background. In fact, Lpar1-null mice backcrossed with C57Bl/6J or C57Bl/6NCr mice showed decreased survival in Dr. Chun’s group and in our colony (see Reference 7 and our unpublished observation). By contrast, another strain called the “Malaga variant” or maLPA1-null mice, which arose spontane-ously from original Lpar1-null mice, demonstrated a more severe phenotype during brain development and in adulthood (49). The maLPA1-null mice dem-onstrated reduced neuroblast proliferation and increased apoptosis in cortical layers, leading to a reduction in cortical thickness. These phenotypes may be
404 NEURAL EFFECTS OF LPA SIGNALING
related to behavioral defects and histological alterations observed in the ento-rhinal cerebral cortex, as described below.
Neurogenesis persists in several regions of the adult mammalian brain including dentate gyrus (DG) (50–52). Neurogenesis in DG is thought to be associated with learning, stress, or exercise. Increased learning tasks, an enriched environment, and voluntary exercise stimulate the DG to produce new neurons through the action of many growth factors. Although maLPA1-null mice showed no obvious phenotype in adult hippocampus, reduced adult neurogenesis in the DG was observed after exposure of the mice to enriched environment and voluntary exercise, compared with that in wild-type mice (53). Compared with wild-type mice, these maLPA1-null mice also showed decreased levels of brain-derived neurotrophic factor (BDNF) and increased levels of both nerve growth factor and insulin-like growth factor after envi-ronmental stimulation. Intriguingly, microglia were reported to be a source of BDNF in response to LPA stimulation (54). It would be interesting to examine the mechanisms by which LPA1 receptors regulate growth factor expression, particularly to determine whether the reduction of growth factor levels in Lpar1-null mice underlies the decreased neurogenesis in DG.
18.2.3. Neurite Outgrowth
Neurites sprout from areas of spherical neurons in culture and grow as pre-sumptive axon and dendrites to establish neuronal polarity (55). The location of centrosomes, endosomes, and the Golgi apparatus is involved in such polar-ity establishment prior to neurite sprouting (56). We recently reported that LPA regulated the position of the Golgi apparatus to influence neuronal polar-ity establishment in immature hippocampal neurons before neurite sprouting occurred (57). Although its molecular mechanisms have not been addressed, this study indicates that LPA acts at the very early developmental stage of neurons.
One major effect of LPA in the nervous system is transient neurite retrac-tion and growth cone collapse in many types of neuronal cells, including neu-roblastoma cells and primary neurons from the central and peripheral nervous system (2, 58–62). LPA1, LPA2, LPA4, LPA5, and LPA6 receptors are capable of mediating LPA-induced neurite retraction responses when overexpressed in rat B103 neuroblastoma cells that show no obvious cellular response to LPA exposure (34, 63–67). The common molecular mechanism underlying neurite retraction is LPA receptor-coupled G12/13 protein activation of the small GTPase Rho, which, in turn, stimulates Rho-associated kinase or ROCK (5, 7, 64). This kinase activation then induces actomyosin contraction, pulling neurites back toward cell bodies. This actin-dependent force also seemed to induce the retrograde transport of microtubules as well as intermediate fila-ments toward cell bodies (68–70). These studies indicate that such cytoskeletal rearrangements occur in harmony during LPA-induced neurite retraction and cell rounding.
LPA SIGNALING IN THE ADULT NERvOUS SYSTEM 405
As neurons matured, neurites extended and no longer responded to LPA with complete retraction (60). Instead, they showed collapse or turning of axonal growth cones in response to LPA (60, 61, 71–73). LPA-induced growth cone collapse utilized Rho-dependent mechanisms in chick dorsal root neurons and Rho-independent mechanisms in cortical neurons. In the latter case, treat-ment of neuronal cells with LPA induced a transient increase in intracellular Ca2+ concentrations, leading to the activation of α-actinin, a Ca2+-binding protein present in growth cones (61). Activated α-actinin then enhanced depo-lymerization of filamentous actin underlying growth cone shapes, resulting in their collapse.
Exogenous expression of LPA1 or LPA2 in B103 cells indicated that these receptors may be involved in Ca2+-mediated growth cone collapse. Another mechanism of LPA-induced growth cone collapse involved local protein deg-radation within growth cones of Xenopus retinal neurons (71, 72). This protein degradation was mediated through activation of p38 MAP kinase and caspase-3, although the involved LPA receptor subtypes remain to be determined. The brains of LPA receptor gene-null mice, however, showed no clear morphologi-cal changes in neurites or neuronal shapes. Furthermore, primary cortical neurons from Lpar1-null mice still demonstrated LPA-induced neurite retrac-tion in vitro (60). Closer analyses of other Lpar-null mice are required.
In contrast to the inhibitory effects of LPA on neurite outgrowth, cyclic PA (cPA), a naturally occurring LPA receptor agonist and ATX inhibitor pro-duced through ATX-mediated catalysis, showed neurotrophic factor-like activ-ity in hippocampal neurons (74–76). In addition, LPA3 activation in neuronal cells seemed to promote neurite outgrowth (65). Lpar3 is transiently expressed in the mouse cerebral cortex and hippocampus during postnatal development, when neurite outgrowth and synapse formation are actively progressing (77). Thus, LPA3 may play a distinct role from other LPA receptors in the nervous system.
18.3. LPA SIGNALING IN THE ADULT NERVOUS SYSTEM
The role of LPA signaling in peripheral nociception was first demonstrated in the adult nervous system (16, 78). By contrast, little is known about the role of LPA signaling in higher brain functions, such as memory, learning, and emotion. However, studies of Lpar-null mice and altered LPAR1, LPAR2, or ENPP2 gene expression in patients carrying neuronal diseases have recently suggested that LPA signaling does play an important role in brain functions and architectures essential for proper neuronal transmission.
18.3.1. Psychiatric Functions
Two independent lines of Lpar1-null mice have been found to show anxiety-like behavior resembling psychiatric diseases such as schizophrenia (79, 80).
406 NEURAL EFFECTS OF LPA SIGNALING
The mice demonstrated decreased behavioral responses in prepulse inhibition, altered serotonin turnover in the brain, and a reduction in the evoked release of serotonin, glutamate, and GABA in vitro (80, 81). The maLPA1-null mice also exhibited impaired exploration in the open field test and increased anxiety index in the elevated plus maze test (79). Electrophysiological and histological analyses of Lpar1-null mice have provided another possible link between Lpar1 and schizophrenia. Brain rhythm analyses revealed reduced gamma oscillations in the entorhinal cortex of Lpar1-null mice, which is thought to be one of the sites that shows dysfunction in schizophrenia (82). Consistent with this alteration, a reduction in the number of GABA- and parvalbumin-containing neurons was observed in the entorhinal cortex, but not the hip-pocampus (82). Thus, some aspects of schizophrenia may be associated with defects in LPA1-mediated signaling or decreased expression of Lpar1. Interest-ingly, LPAR1 downregulation has been reported in peripheral blood lympho-cytes from schizophrenic patients (83).
How are LPA1 receptors involved in psychiatric functions? Insufficient neurogenesis in the cerebral cortex and hippocampus of Lpar1-null mice sug-gests that LPA1 is necessary for proper neurogenesis during development, leading to the correct establishment of brain architectures that produce normal psychiatric functions. Alternatively, LPA1 receptors may be directly involved in synapse formation or transmission at glutamatergic synapses (84, 85). Tran-scriptional regulation of glutamate receptor genes by LPA1 has also been shown to be associated with cocaine-induced conditioned locomotion (86). Such LPA1-mediated morphological and functional regulation of synapses could be related to psychiatric behaviors. Another possibility involves LPA1-associated regulation of myelination by oligodendrocytes during development and in adulthood, because this glial cell type prominently expresses Lpar1 in the postnatal period (87, 88). LPA1-mediated signaling may be involved in the formation of myelin required for proper psychiatric functions, although abnor-mal myelination has not yet been detected in Lpar1-null mice. Further analy-ses are awaited to unveil the molecular and cellular mechanisms underlying LPA1-dependent regulation of psychiatric functions.
18.3.2. Memory and Learning
In addition to anxiety-like behavior, maLPA1-null mice exhibited spatial memory deficits (79). In the Morris water maze test, an impairment of spatial memory retention was observed in maLPA1-null mice. The memory deficit was more aggravated when these null mice were exposed to chronic stress and assessed in another type of memory test (89). LPA1 receptors may be necessary for the formation of memory-associated neuronal networks through neuro-genesis. LPA1-mediated memory retention may also occur through direct regu-lation of synapse transmission, because intrahippocampal infusion of LPA also enhanced long-term spatial memory, via enhancement of Rho signaling (90). Another indication of the involvement of LPA signaling in memory is that
LPA SIGNALING IN THE ADULT NERvOUS SYSTEM 407
ENPP2 gene expression was greater in the frontal cortex of patients with Alzheimer-type dementia (ATD) than that of control patients (91). This finding suggested that LPA production was enhanced in ATD patients, in contrast to LPA-induced enhancement of memory retention. LPA overpro-duced by upregulated ATX may be sustained, causing some damage in the brain, as described below.
18.3.3. Neuronal Excitation
Remarkable changes in synaptic transmission have been demonstrated in mice lacking the PRG-1 gene (92). PRG-1 was originally isolated as a gene upregulated in the hippocampus after deafferentation between the entorhinal cortex and hippocampus, and was then identified as encoding an enzyme that dephosphorylates LPA at excitatory synapses (93). Functional analyses further revealed that overexpression of PRG-1 in neuronal cells attenuated LPA-induced neurite retraction, indicating that PRG-1 terminated LPA-induced cellular responses through degradation of LPA. A recent study has shown that PRG-1 is able to bind calmodulin, indicating that PRG-1 activity may be regu-lated by the interaction between calmodulin and the large cytoplasmic portion of PRG-1 (94). PRG-1-null mice demonstrated epileptic seizures and enhanced excitatory synaptic transmission around postnatal day 20 (92). This hyperexci-tation diminished in PRG-1/Lpar2-double-null mice. These findings suggest that appropriate LPA signaling, which is mediated by LPA2 receptors and ter-minated by PRG-1 at excitatory synapses, modulates hippocampal excitability through the regulation of synaptic transmission. Indeed, LPA was reported to enhance neurotransmitter release from synaptosome preparations (95).
This study of PRG-1-null mice also demonstrated, for the first time, that LPA2 receptors play a role in synaptic transmission in the nervous system. Because the Lpar2 gene is expressed in the embryonic brain and decreased in the postnatal brain (33, 77), LPA2 is thought to cooperate with PRG-1 to control neuronal excitability, which may be essential for neuronal network formation, during embryonic and postnatal hippocampal development. Although no obvious phenotype has been reported for Lpar2-null mice (20), closer histological and functional analyses may provide us with novel LPA-dependent machinery for brain development or functions.
18.3.4. Brain Injury
Mouse astrocytes in culture expressed Lpar1–5 genes depending on culture conditions (46, 96). Expression of the Lpar6 gene has not yet been determined. LPA was shown to induce a variety of cellular responses in cultured astrocytes, including enhanced cell proliferation and DNA synthesis, cytoskeletal rear-rangement, inhibition of glutamate and glucose uptake, Ca2+ mobilization, reactive oxygen species production, and the production of trophic factors (97–102). The use of Lpar1-null astrocytes revealed that LPA1 receptors
408 NEURAL EFFECTS OF LPA SIGNALING
mediated LPA-induced increased DNA synthesis but not glutamate uptake (96). Furthermore, the neuronal differentiation effects of LPA-primed astro-cytes via trophic factor production were lost when astrocytes were prepared from Lpar1/Lpar2-double-null mice (46). These neurotrophic effects were restored by the introduction of either Lpar1 or Lpar2 to the double-null astrocytes. However, LPA receptor subtypes that mediate other LPA-induced cellular responses remain unknown.
In vivo, mouse astrocytes expressed no or low detectable levels of Lpar1, Lpar2, and Lpar3 genes (87, 103). However, following physical injury to the central nervous system, emerging reactive astrocytes expressed the Lpar1 and Lpar2 genes as well as Enpp2, but not Lpar3 (103, 104). Furthermore, LPA injection into the mouse brain induced generation of reactive astrocytes remi-niscent of those observed following brain injury or stroke (99). Alterations of LPAR2 and ENPP2 gene expression levels were also reported in the human cerebral cortex following injury (105). Because LPA is produced by activated platelets, the destruction of brain vessels may expose the brain to platelet-derived, leaked LPA and other mediators, resulting in the activation of astro-cytes (106). Reactive astrocytes may then exhibit LPA-induced responses as well as LPA production. Thus, LPA signaling plays an autocrine or paracrine role in astrocyte-mediated responses during injury.
Microglia also expressed Lpar1 or Lpar3 in culture, depending on the species or activation state, and responded to LPA with Ca2+ mobilization, ATP release, and BDNF expression (54, 107, 108). However, these glia showed no expression of Lpar1, Lpar2, or Lpar3 genes in intact or injured central nervous system (103). The expression of non-edg LPA receptor genes in microglia remains to be determined. A recent study demonstrated the involvement of in vivo microglial activation in sciatic nerve injury, where LPA derived from activated microglia mediated the initiation of neuropathic pain (109) (also see below).
18.3.5. Peripheral Sensory Functions
The ATX-LPA1 axis has been shown to have pathological significance in the initiation of neuropathic pain, as manifested by hyperalgesia and tactile allo-dynia, and its underlying demyelination of sensory neurons (78, 110). The intrathecal injection of LPA into mice induced neuropathic pain along with the upregulation of protein kinase Cγ and α2δ1 calcium channel subunit in the spinal cord dorsal horn and dorsal root ganglia, respectively, as well as the demyelination of the dorsal root. Similar changes were produced by nerve injury with a partial sciatic nerve ligation method (111). These LPA-induced changes were attenuated by inhibition of Rho and were also absent in Lpar1-null mice. LPA1 receptors were also likely to mediate reorganization of Aβ sensory fibers associated with neuropathic allodynia (112).
Like LPA, intrathecal lysophosphatidylcholine (LPC) injection also induced neuropathic pain and demyelination, which were attenuated in
FUTURE DIRECTIONS 409
ATX-heterozygous mutant mice and abolished in Lpar1-null mice, suggesting that ATX-mediated LPA production occurs in nerve injury (113). This might be supported by the finding that cPA treatment attenuated neuropathic pain in mice (114). Recent studies have shown that nerve injury indeed triggered de novo LPA production in the spinal cord through activation of phospholipase A2 and ATX (115). Furthermore, LPA3 receptors were likely to be involved in LPA-induced LPA production, presumably in microglia (109, 116). Taken together, these observations suggest that nerve injury initiates LPA production via ATX-mediated conversion from LPC, followed by LPA3 receptor-dependent LPA production. Locally produced LPA then causes demyelination and reor-ganization of Aβ fibers through LPA1 receptors. LPA1 signaling was also involved in bone cancer-induced mechanical allodynia and thermal hyperalge-sia through activation of transient receptor potential vanilloid 1 in the dorsal root ganglion (117, 118).
Neuropathic pain-associated demyelination in the dorsal root, accompanied by downregulation of myelin proteins, was shown to be a direct action of LPA on Schwann cells (119, 120). LPA1-mediated signaling was involved in morphological changes to Schwann cells in vitro, from bipolar shapes with elongated processes to flattened shapes without processes (121), and these morphological changes may underlie in vivo demyelination. However, LPA1-mediated signaling was also demonstrated in Schwann cell development and survival (19, 122). Thus, LPA1 may play two distinct developmental and patho-physiological roles in the sensory nervous system.
Another possible sensory function involving LPA signaling is itchiness. Cholestasis is caused by dysfunction of bile flow and has many associated symptoms, including jaundice, light-colored stool, and itchiness. LPA and ATX concentrations were increased in sera from cholestatic patients with itchiness, and ATX activity correlated with the intensity of itchiness (123–125). Further-more, intradermal injection of LPA elicited scratch responses in mice, which seemed to be mediated by histamine release from mast cells (123, 126, 127). These data implicate LPA as an indirect signaling mediator for itchiness.
18.4. FUTURE DIRECTIONS
Advancements in LPA research in roughly two decades since the first report showing LPA-induced cell proliferation include the improvement of LPA signaling assay systems, the generation of genetically engineered mice lacking genes for LPA receptors or LPA-signaling and related enzymes, and the devel-opment of synthetic compounds that act specifically on LPA receptors or enzymes. This review has discussed the roles of LPA signaling in the nervous system, based on the experimental observations conducted using such advance-ments and the implications from analyses of human clinical samples. Studies clearly demonstrate that LPA signaling is markedly complicated but of great developmental, physiological, and pathological significance to the central and
410 NEURAL EFFECTS OF LPA SIGNALING
peripheral nervous system, and that abnormal LPA signaling may result in developmental, psychiatric, or sensory disorders in humans. Therefore, LPA signaling may be a therapeutic target for these diseases. Future studies are necessary to further uncover roles of LPA signaling in the nervous system, which could lead to the development of therapeutic drugs targeting LPA signaling.
ACKNOWLEDGMENTS
This work was supported by grants-in-aid from the MEXT and research grants from Kinki University.
REFERENCES
1. van Corven EJ, Groenink A, Jalink K, Eichholtz T, Moolenaar WH. 1989. Lysophosphatidate-induced cell proliferation: identification and dissection of sig-naling pathways mediated by G proteins. Cell 59:45–54.
2. Hecht JH, Weiner JA, Post SR, Chun J. 1996. Ventricular zone gene-1 (vzg-1) encodes a lysophosphatidic acid receptor expressed in neurogenic regions of the developing cerebral cortex. J Cell Biol 135:1071–1083.
3. Fukushima N, Ishii I, Contos JA, Weiner JA, Chun J. 2001. Lysophospholipid receptors. Annu Rev Pharmacol Toxicol 41:507–534.
4. Fukushima N. 2004. LPA in neural cell development. J Cell Biochem 92:993–1003.
5. Noguchi K, Herr D, Mutoh T, Chun J. 2009. Lysophosphatidic acid (LPA) and its receptors. Curr Opin Pharmacol 9:15–23.
6. Ishii I, Fukushima N, Ye X, Chun J. 2004. Lysophospholipid receptors: signaling and biology. Annu Rev Biochem 73:321–354.
7. Choi JW, Herr DR, Noguchi K, Yung YC, Lee CW, et al. 2010. LPA receptors: subtypes and biological actions. Annu Rev Pharmacol Toxicol 50:157–186.
8. Ishii S, Noguchi K, Yanagida K. 2009. Non-Edg family lysophosphatidic acid (LPA) receptors. Prostaglandins Other Lipid Mediat 89:57–65.
9. Chun J, Hla T, Lynch KR, Spiegel S, Moolenaar WH. 2010. International union of basic and clinical pharmacology. LXXVIII. Lysophospholipid receptor nomencla-ture. Pharmacol Rev 62:579–587.
10. Nakanaga K, Hama K, Aoki J. 2010. Autotaxin—an LPA producing enzyme with diverse functions. J Biochem (Tokyo) 148:13–24.
11. Aoki J, Inoue A, Okudaira S. 2008. Two pathways for lysophosphatidic acid pro-duction. Biochim Biophys Acta 1781:513–518.
12. Brauer AU, Nitsch R. 2008. Plasticity-related genes (PRGs/LRPs): a brain-specific class of lysophospholipid-modifying proteins. Biochim Biophys Acta 1781:595–600.
13. Brindley DN, English D, Pilquil C, Buri K, Ling ZC. 2002. Lipid phosphate phos-phatases regulate signal transduction through glycerolipids and sphingolipids. Biochim Biophys Acta 1582:33–44.
REFERENCES 411
14. Lin ME, Herr DR, Chun J. 2010. Lysophosphatidic acid (LPA) receptors: signaling properties and disease relevance. Prostaglandins Other Lipid Mediat 91:130–138.
15. Choi JW, Lee CW, Chun J. 2008. Biological roles of lysophospholipid receptors revealed by genetic null mice: an update. Biochim Biophys Acta 1781:531–539.
16. Ueda H. 2011. Lysophosphatidic acid as the initiator of neuropathic pain. Biol Pharm Bull 34:1154–1158.
17. Ohuchi H, Hamada A, Matsuda H, Takagi A, Tanaka M, et al. 2008. Expression patterns of the lysophospholipid receptor genes during mouse early development. Dev Dyn 237:3280–3294.
18. Ye X, Hama K, Contos JJ, Anliker B, Inoue A, et al. 2005. LPA3-mediated lyso-phosphatidic acid signalling in embryo implantation and spacing. Nature 435:104–108.
19. Contos JJA, Fukushima N, Weiner JA, Kaushal D, Chun J. 2000. Requirement for the lpA1 lysophosphatidic acid receptor gene in normal suckling behavior. Proc Natl Acad Sci U S A 97:13384–13389.
20. Contos JJA, Ishii I, Fukushima N, Kingsbury MA, Ye X, et al. 2002. Characteriza-tion of lpa2 (Edg4) and lpa1/lpa2 (Edg2/Edg4) lysophosphatidic acid receptor knockout mice: signaling deficits without obvious phenotypic abnormality attrib-utable to LPA2. Mol Cell Biol 22:6921–6929.
21. Lee Z, Cheng CT, Zhang H, Subler MA, Wu J, et al. 2008. Role of LPA4/p2y9/GPR23 in negative regulation of cell motility. Mol Biol Cell 19:5435–5445.
22. Sumida H, Noguchi K, Kihara Y, Abe M, Yanagida K, et al. 2010. LPA4 regulates blood and lymphatic vessel formation during mouse embryogenesis. Blood 116:5060–5070.
23. Tanaka M, Okudaira S, Kishi Y, Ohkawa R, Iseki S, et al. 2006. Autotaxin stabilizes blood vessels and is required for embryonic vasculature by producing lysophos-phatidic acid. J Biol Chem 281:25822–25830.
24. Fotopoulou S, Oikonomou N, Grigorieva E, Nikitopoulou I, Paparountas T, et al. 2010. ATX expression and LPA signalling are vital for the development of the nervous system. Dev Biol 339:451–464.
25. van Meeteren LA, Ruurs P, Stortelers C, Bouwman P, van Rooijen MA, et al. 2006. Autotaxin, a secreted lysophospholipase D, is essential for blood vessel formation during development. Mol Cell Biol 26:5015–5022.
26. Escalante-Alcalde D, Hernandez L, Le Stunff H, Maeda R, Lee HS, et al. 2003. The lipid phosphatase LPP3 regulates extra-embryonic vasculogenesis and axis patterning. Development 130:4623–4637.
27. Zhang N, Sundberg JP, Gridley T. 2000. Mice mutant for Ppap2c, a homolog of the germ cell migration regulator wunen, are viable and fertile. Genesis 27:137–140.
28. Yue JM, Yokoyama K, Balazs L, Baker DL, Smalley D, et al. 2004. Mice with transgenic overexpression of lipid phosphate phosphatase-1 display multiple organotypic deficits without alteration in circulating lysophosphatidate level. Cell Signal 16:385–399.
29. Yung YC, Mutoh T, Lin M-E, Noguchi K, Rivera RR, et al. 2011. Lysophosphatidic acid signaling may initiate fetal hydrocephalus. Sci Transl Med 3:99ra87.
30. Del Bigio MR. 2010. Neuropathology and structural changes in hydrocephalus. Dev Disabil Res Rev 16:16–22.
412 NEURAL EFFECTS OF LPA SIGNALING
31. Thompson DN. 2009. Postnatal management and outcome for neural tube defects including spina bifida and encephalocoeles. Prenat Diagn 29:412–419.
32. Dubin AE, Herr DR, Chun J. 2010. Diversity of lysophosphatidic acid receptor-mediated intracellular calcium signaling in early cortical neurogenesis. J Neurosci 30:7300–7309.
33. Contos JJA, Chun J. 2000. Genomic characterization of the lysophosphatidic acid receptor gene, lpA2/Edg4, and identification of a frameshift mutation in a previ-ously characterized cDNA. Genomics 64:155–169.
34. Lee CW, Rivera R, Dubin AE, Chun J. 2007. LPA4/GPR23 is a lysophosphatidic acid (LPA) receptor utilizing Gs-, Gq/Gi-mediated calcium signaling and G12/13-mediated Rho activation. J Biol Chem 282:4310–4317.
35. Fukushima N, Weiner JA, Chun J. 2000. Lysophosphatidic acid (LPA) is a novel extracellular regulator of cortical neuroblast morphology. Dev Biol 228:6–18.
36. Dubin AE, Bahnson T, Weiner JA, Fukushima N, Chun J. 1999. Lysophosphatidic acid stimulates neurotransmitter-like conductance changes that precede GABA and L-glutamate in early, presumptive cortical neuroblasts. J Neurosci 19:1371–1381.
37. Owens DF, Kriegstein AR. 1998. Patterns of intracellular calcium fluctuation in precursor cells of the neocortical ventricular zone. J Neurosci 18:5374–5388.
38. Faure AV, Grunwald D, Moutin MJ, Hilly M, Mauger JP, et al. 2001. Developmen-tal expression of the calcium release channels during early neurogenesis of the mouse cerebral cortex. Eur J Neurosci 14:1613–1622.
39. Weissman TA, Riquelme PA, Ivic L, Flint AC, Kriegstein AR. 2004. Calcium waves propagate through radial glial cells and modulate proliferation in the developing neocortex. Neuron 43:647–661.
40. Kingsbury MA, Rehen SK, Contos JJ, Higgins CM, Chun J. 2003. Non-proliferative effects of lysophosphatidic acid enhance cortical growth and folding. Nat Neurosci 6:1292–1299.
41. Fukushima N, Shano S, Moriyama R, Chun J. 2007. Lysophosphatidic acid stimu-lates neuronal differentiation of cortical neuroblasts through the LPA1-Gi/o pathway. Neurochem Int 50:302–307.
42. Svetlov SI, Ignatova TN, Wang KK, Hayes RL, English D, Kukekov VG. 2004. Lysophosphatidic acid induces clonal generation of mouse neurospheres via pro-liferation of Sca-1- and AC133-positive neural progenitors. Stem Cells Dev 13:685–693.
43. Dottori M, Leung J, Turnley AM, Pebay A. 2008. Lysophosphatidic acid inhibits neuronal differentiation of neural stem/progenitor cells derived from human embryonic stem cells. Stem Cells 26:1146–1154.
44. Pitson SM, Pebay A. 2009. Regulation of stem cell pluripotency and neural dif-ferentiation by lysophospholipids. Neurosignals 17:242–254.
45. Herr KJ, Herr DR, Lee C-W, Noguchi K, Chun J. 2011. Stereotyped fetal brain disorganization is induced by hypoxia and requires lysophosphatidic acid receptor 1 (LPA1) signaling. Proc Natl Acad Sci U S A 108:15444–25449.
46. Spohr TC, Choi JW, Gardell SE, Herr DR, Rehen SK, et al. 2008. Lysophosphatidic acid receptor-dependent secondary effects via astrocytes promote neuronal dif-ferentiation. J Biol Chem 283:7470–7479.
REFERENCES 413
47. Leite de Sampaio e Spohr TC, Dezonne RS, Rehen SK, Alcantara Gomes FC. 2011. Astrocytes treated by lysophosphatidic acid induce axonal outgrowth of cortical progenitors through extracellular matrix protein and epidermal growth factor signaling pathway. J Neurochem 119:113–123.
48. McGiffert C, Contos JJ, Friedman B, Chun J. 2002. Embryonic brain expression analysis of lysophospholipid receptor genes suggests roles for s1p1 in neurogenesis and s1p1-3 in angiogenesis. FEBS Lett 531:103–108.
49. Estivill-Torrus G, Llebrez-Zayas P, Matas-Rico E, Santin L, Pedraza C, et al. 2008. Absence of LPA1 signaling results in defective cortical development. Cereb Cortex 18:938–950.
50. Christie BR, Cameron HA. 2006. Neurogenesis in the adult hippocampus. Hip-pocampus 16:199–207.
51. Zhao CM, Deng W, Gage FH. 2008. Mechanisms and functional implications of adult neurogenesis. Cell 132:645–660.
52. Deng W, Aimone JB, Gage FH. 2010. New neurons and new memories: how does adult hippocampal neurogenesis affect learning and memory? Nat Rev Neurosci 11:339–350.
53. Matas-Rico E, Garcia-Diaz B, Llebrez-Zayas P, Lopez-Barroso D, Santin L, et al. 2008. Deletion of lysophosphatidic acid receptor LPA1 reduces neurogenesis in the mouse dentate gyrus. Mol Cell Neurosci 39:342–355.
54. Fujita R, Ma Y, Ueda H. 2008. Lysophosphatidic acid-induced membrane ruffling and brain-derived neurotrophic factor gene expression are mediated by ATP release in primary microglia. J Neurochem 107:152–160.
55. Arimura N, Kaibuchi K. 2007. Neuronal polarity: from extracellular signals to intracellular mechanisms. Nat Rev Neurosci 8:194–205.
56. de Anda FC, Pollarolo G, Da Silva JS, Camoletto PG, Feiguin F, Dotti CG. 2005. Centrosome localization determines neuronal polarity. Nature 436:704–708.
57. Yamane M, Furuta D, Fukushima N. 2010. Lysophosphatidic acid influences initial neuronal polarity establishment. Neurosci Lett 480:154–157.
58. Jalink K, Eichholtz T, Postma FR, van Corven EJ, Moolenaar WH. 1993. Lyso-phosphatidic acid induces neuronal shape changes via a novel, receptor-mediated signaling pathway: similarity to thrombin action. Cell Growth Differ 4:247–255.
59. Tigyi G, Miledi R. 1992. Lysophosphatidates bound to serum albumin activate membrane currents in Xenopus oocytes and neurite retraction in PC12 pheochro-mocytoma cells. J Biol Chem 267:21360–21367.
60. Fukushima N, Weiner JA, Kaushal D, Contos JJA, Rehen SK, et al. 2002. Lyso-phosphatidic acid influences the morphology and motility of young, postmitotic cortical neurons. Mol Cell Neurosci 20:271–282.
61. Fukushima N, Ishii I, Habara Y, Allen CB, Chun J. 2002. Dual regulation of actin rearrangement through lysophosphatidic acid receptor in neuroblast cell lines: actin depolymerization by Ca2+-α-actinin and polymerization by Rho. Mol Biol Cell 13:2692–2705.
62. Saito S. 1997. Effects of lysophosphatidic acid on primary cultured chick neurons. Neurosci Lett 229:73–76.
63. Yanagida K, Ishii S, Hamano F, Noguchi K, Shimizu T. 2007. LPA4/p2y9/GPR23 mediates Rho-dependent morphological changes in a rat neuronal cell line. J Biol Chem 282:5814–5824.
414 NEURAL EFFECTS OF LPA SIGNALING
64. Yanagida K, Masago K, Nakanishi H, Kihara Y, Hamano F, et al. 2009. Identifica-tion and characterization of a novel lysophosphatidic acid receptor, p2y5/LPA6. J Biol Chem 284:17731–17741.
65. Ishii I, Contos JJ, Fukushima N, Chun J. 2000. Functional comparisons of the lysophosphatidic acid receptors, LPA1/VZG-1/EDG-2, LPA2/EDG-4, and LPA3/EDG-7 in neuronal cell lines using a retrovirus expression system. Mol Pharmacol 58:895–902.
66. Lee CW, Rivera R, Gardell S, Dubin AE, Chun J. 2006. GPR92 as a new G12/13 and Gq coupled lysophosphatidic acid receptor that increases cAMP: LPA5. J Biol Chem 281:23589–23597.
67. Fukushima N, Kimura Y, Chun J. 1998. A single receptor encoded by vzg-1/lpA1/edg-2 couples to G proteins and mediates multiple cellular responses to lysophos-phatidic acid. Proc Natl Acad Sci U S A 95:6151–6156.
68. Bouquet C, Ravaille-Veron M, Propst F, Nothias F. 2007. MAP1B coordinates microtubule and actin filament remodeling in adult mouse Schwann cell tips and DRG neuron growth cones. Mol Cell Neurosci 36:235–247.
69. Fukushima N, Morita Y. 2006. Actomyosin-dependent microtubule rearrangement in lysophosphatidic acid-induced neurite remodeling of young cortical neurons. Brain Res 1094:65–75.
70. Fukushima N, Furuta D, Tsujiuchi T. 2011. Coordinated interactions between actin and microtubules through crosslinkers in neurite retraction induced by lysophos-phatidic acid. Neurochem Int 59:109–113.
71. Campbell DS, Holt CE. 2001. Chemotropic responses of retinal growth cones mediated by rapid local protein synthesis and degradation. Neuron 32:1013–1026.
72. Campbell DS, Holt CE. 2003. Apoptotic pathway and MAPKs differentially regu-late chemotropic responses of retinal growth cones. Neuron 37:939–952.
73. Yuan XB, Jin M, Xu X, Song YQ, Wu CP, et al. 2003. Signalling and crosstalk of Rho GTPases in mediating axon guidance. Nat Cell Biol 5:38–45.
74. Fujiwara Y, Sebok A, Meakin S, Kobayashi T, Murakami-Murofushi K, Tigyi G. 2003. Cyclic phosphatidic acid elicits neurotrophin-like actions in embryonic hip-pocampal neurons. J Neurochem 87:1272–1283.
75. Tsuda S, Okudaira S, Moriya-Ito K, Shimamoto C, Tanaka M, et al. 2006. Cyclic phosphatidic acid is produced by autotaxin in blood. J Biol Chem 281:26081–26088.
76. Baker DL, Fujiwara Y, Pigg KR, Tsukahara R, Kobayashi S, et al. 2006. Carba analogs of cyclic phosphatidic acid are selective inhibitors of autotaxin and cancer cell invasion and metastasis. J Biol Chem 281:22786–22793.
77. Contos JJA, Ishii I, Chun J. 2000. Lysophosphatidic acid receptors. Mol Pharmacol 58:1188–1196.
78. Ueda H. 2006. Molecular mechanisms of neuropathic pain-phenotypic switch and initiation mechanisms. Pharmacol Ther 109:57–77.
79. Santin LJ, Bilbao A, Pedraza C, Matas-Rico E, Lopez-Barroso D, et al. 2009. Behavioral phenotype of maLPA1-null mice: increased anxiety-like behavior and spatial memory deficits. Genes Brain Behav 8:772–784.
REFERENCES 415
80. Harrison SM, Reavill C, Brown G, Brown JT, Cluderay JE, et al. 2003. LPA1 receptor-deficient mice have phenotypic changes observed in psychiatric disease. Mol Cell Neurosci 24:1170–1179.
81. Roberts C, Winter P, Shilliam CS, Hughes ZA, Langmead C, et al. 2005. Neuro-chemical changes in LPA1 receptor deficient mice—a putative model of schizo-phrenia. Neurochem Res 30:371–377.
82. Cunningham MO, Hunt J, Middleton S, LeBeau FEN, Gillies MG, et al. 2006. Region-specific reduction in entorhinal gamma oscillations and parvalbumin-immunoreactive neurons in animal models of psychiatric illness. J Neurosci 26:2767–7276.
83. Bowden NA, Weidenhofer J, Scott RJ, Schall U, Todd J, et al. 2006. Preliminary investigation of gene expression profiles in peripheral blood lymphocytes in schizophrenia. Schizophr Res 82:175–183.
84. Pilpel Y, Segal M. 2006. The role of LPA1 in formation of synapses among cultured hippocampal neurons. J Neurochem 97:1379–1392.
85. Musazzi L, Di Daniel E, Maycox P, Racagni G, Popoli M. 2011. Abnormalities in α/β-CaMKII and related mechanisms suggest synaptic dysfunction in hippocam-pus of LPA1 receptor knockout mice. Int J Neuropsychopharmacol 14:941–953.
86. Blanco E, Bilbao A, Luque-Rojas MJ, Palomino A, Bermudez-Silva FJ, et al. 2011. Attenuation of cocaine-induced conditioned locomotion is associated with altered expression of hippocampal glutamate receptors in mice lacking LPA1 receptors. Psychopharmacology (Berl) (epub ahead of print 2011 Sep 2).
87. Weiner JA, Hecht JH, Chun J. 1998. Lysophosphatidic acid receptor gene vzg-1/lpA1/edg-2 is expressed by mature oligodendrocytes during myelination in the postnatal murine brain. J Comp Neurol 398:587–598.
88. Allard J, Barraon S, Diaz J, Lubetzki C, Zalc B, et al. 1998. A rat G protein-coupled receptor selectively expressed in myelin-forming cells. Eur J Neurosci 10:1045–1053.
89. Castilla-Ortega E, Hoyo-Becerra C, Pedraza C, Chun J, Rodriguez De Fonseca F, et al. 2011. Aggravation of chronic stress effects on hippocampal neurogenesis and spatial memory in LPA1 receptor knockout mice. PLoS ONE 6:e25522.
90. Dash PK, Orsi SA, Moody M, Moore AN. 2004. A role for hippocampal Rho-ROCK pathway in long-term spatial memory. Biochem Biophys Res Commun 322:893–898.
91. Umemura K, Yamashita N, Yu X, Arima K, Asada T, et al. 2006. Autotaxin expres-sion is enhanced in frontal cortex of Alzheimer-type dementia patients. Neurosci Lett 400:97–100.
92. Trimbuch T, Beed P, Vogt J, Schuchmann S, Maier N, et al. 2009. Synaptic PRG-1 modulates excitatory transmission via lipid phosphate-mediated signaling. Cell 138:1222–1235.
93. Brauer AU, Savaskan NE, Kuhn H, Prehn S, Ninnemann O, Nitsch R. 2003. A new phospholipid phosphatase, PRG-1, is involved in axon growth and regenerative sprouting. Nat Neurosci 6:572–578.
94. Tokumitsu H, Hatano N, Tsuchiya M, Yurimoto S, Fujimoto T, et al. 2010. Identi-fication and characterization of PRG-1 as a neuronal calmodulin-binding protein. Biochem J 431:81–91.
416 NEURAL EFFECTS OF LPA SIGNALING
95. Nishikawa T, Tomori Y, Yamashita S, Shimizu SI. 1989. Inhibition of Na+, K+-ATPase activity by phospholipase-A2 and several lysophospholipids—possible role of phospholipase-A2 in noradrenaline release from cerebral cortical synap-tosomes. J Pharm Pharmacol 41:450–458.
96. Shano S, Moriyama R, Chun J, Fukushima N. 2008. Lysophosphatidic acid stimu-lates astrocyte proliferation through LPA1. Neurochem Int 52:216–220.
97. Keller JN, Steiner MR, Mattson MP, Steiner SM. 1996. Lysophosphatidic acid decreases glutamate and glucose uptake by astrocytes. J Neurochem 67:2300–2305.
99. Sorensen SD, Nicole O, Peavy RD, Montoya LM, Lee CJ, et al. 2003. Common signaling pathways link activation of murine PAR-1, LPA, and S1P receptors to proliferation of astrocytes. Mol Pharmacol 64:1199–1209.
100. Rao TS, Lariosa-Willingham KD, Lin FF, Palfreyman EL, Yu N, et al. 2003. Phar-macological characterization of lysophospholipid receptor signal transduction pathways in rat cerebrocortical astrocytes. Brain Res 990:182–194.
101. Manning TJJ, Sontheimer H. 1997. Bovine serum albumin and lysophosphatidic acid stimulate calcium mobilization and reversal of cAMP-induced stellation in rat spinal cord astrocytes. Glia 20:163–172.
102. Suidan H, Nobes C, Hall A, Monard D. 1997. Astrocyte spreading in response to thrombin and lysophosphatidic acid is dependent on the Rho GTPase. Glia 21:244–252.
103. Goldshmit Y, Munro K, Leong SY, Pebay A, Turnley AM. 2010. LPA receptor expression in the central nervous system in health and following injury. Cell Tissue Res 341:23–32.
104. Savaskan NE, Rocha L, Kotter MR, Baer A, Lubec G, et al. 2007. Autotaxin (NPP-2) in the brain: cell type-specific expression and regulation during development and after neurotrauma. Cell Mol Life Sci 64:230–243.
105. Frugier T, Crombie D, Conquest A, Tjhong F, Taylor C, et al. 2011. Modulation of LPA receptor expression in the human brain following neurotrauma. Cell Mol Neurobiol 31:569–577.
106. Eichholtz T, Jalink K, Fahrenfort I, Moolenaar WH. 1993. The bioactive phospho-lipid lysophosphatidic acid is released from activated platelets. Biochem J 291:677–680.
107. Moller T, Contos JJ, Musante DB, Chun J, Ransom BR. 2001. Expression and function of lysophosphatidic acid receptors in cultured rodent microglial cells. J Biol Chem 276:25946–25952.
108. Tham CS, Lin FF, Rao TS, Yu N, Webb M. 2003. Microglial activation state and lysophospholipid acid receptor expression. Int J Dev Neurosci 21:431–443.
109. Ma L, Nagai J, Ueda H. 2010. Microglial activation mediates de novo lysophos-phatidic acid production in a model of neuropathic pain. J Neurochem 115:643–653.
110. Ueda H. 2008. Peripheral mechanisms of neuropathic pain—involvement of lyso-phosphatidic acid receptor-mediated demyelination. Mol Pain 4:11.
REFERENCES 417
111. Inoue M, Rashid MH, Fujita R, Contos JJ, Chun J, Ueda H. 2004. Initiation of neuropathic pain requires lysophosphatidic acid receptor signaling. Nat Med 10:712–718.
112. Xie W, Matsumoto M, Chun J, Ueda H. 2008. Involvement of LPA1 receptor signaling in the reorganization of spinal input through Abeta-fibers in mice with partial sciatic nerve injury. Mol Pain 4:46.
113. Inoue M, Xie W, Matsushita Y, Chun J, Aoki J, Ueda H. 2008. Lysophosphatidyl-choline induces neuropathic pain through an action of autotaxin to generate lysophosphatidic acid. Neuroscience 152:296–298.
114. Kakiuchi Y, Nagai J, Gotoh M, Hotta H, Murofushi H, et al. 2011. Antinociceptive effect of cyclic phosphatidic acid and its derivative on animal models of acute and chronic pain. Mol Pain 7:33.
115. Ma L, Uchida H, Nagai J, Inoue M, Aoki J, Ueda H. 2010. Evidence for de novo synthesis of lysophosphatidic acid in the spinal cord through phospholipase A2 and autotaxin in nerve injury-induced neuropathic pain. J Pharmacol Exp Ther 333:540–546.
116. Ma L, Uchida H, Nagai J, Inoue M, Chun J, et al. 2009. Lysophosphatidic acid-3 receptor-mediated feed-forward production of lysophosphatidic acid: an initiator of nerve injury-induced neuropathic pain. Mol Pain 5:64.
117. Pan HL, Zhang YQ, Zhao ZQ. 2010. Involvement of lysophosphatidic acid in bone cancer pain by potentiation of TRPV1 via PKC pathway in dorsal root ganglion neurons. Mol Pain 6:85.
118. Zhao J, Pan HL, Li TT, Zhang YQ, Wei JY, Zhao ZQ. 2010. The sensitization of peripheral C-fibers to lysophosphatidic acid in bone cancer pain. Life Sci 87:120–125.
119. Xie W, Uchida H, Nagai J, Ueda M, Chun J, Ueda H. 2010. Calpain-mediated down-regulation of myelin-associated glycoprotein in lysophosphatidic acid-induced neuropathic pain. J Neurochem 113:1002–1011.
120. Fujita R, Kiguchi N, Ueda H. 2007. LPA-mediated demyelination in ex vivo culture of dorsal root. Neurochem Int 50:351–355.
121. Weiner JA, Fukushima N, Contos JJA, Scherer SS, Chun J. 2001. Regulation of Schwann cell morphology and adhesion by receptor-mediated lysophosphatidic acid signaling. J Neurosci 21:7069–7078.
122. Weiner JA, Chun J. 1999. Schwann cell survival mediated by the signaling phos-pholipid lysophosphatidic acid. Proc Natl Acad Sci U S A 96:5233–5238.
123. Kremer AE, Martens JJ, Kulik W, Rueff F, Kuiper EM, et al. 2010. Lysophospha-tidic acid is a potential mediator of cholestatic pruritus. Gastroenterology 139:1008–1018.
124. Oude Elferink RP, Kremer AE, Beuers U. 2011. Mediators of pruritus during cholestasis. Curr Opin Gastroenterol 27:289–293.
125. Oude Elferink RP, Kremer AE, Martens JJ, Beuers UH. 2011. The molecular mechanism of cholestatic pruritus. Dig Dis 29:66–71.
126. Kim HJ, Kim H, Han ES, Park SM, Koh JY, et al. 2008. Characterizations of sphingosylphosphorylcholine-induced scratching responses in ICR mice using nal-trexon, capsaicin, ketotifen and Y-27632. Eur J Pharmacol 583:92–96.
127. Hashimoto T, Ohata H, Momose K. 2004. Itch-scratch responses induced by lyso-phosphatidic acid in mice. Pharmacology 72:51–56.
418 NEURAL EFFECTS OF LPA SIGNALING
128. Inoue M, Ma L, Aoki J, Chun J, Ueda H. 2008. Autotaxin, a synthetic enzyme of lysophosphatidic acid (LPA), mediates the induction of nerve-injured neuropathic pain. Mol Pain 4:6.
129. Nagai J, Uchida H, Matsushita Y, Yano R, Ueda M, et al. 2010. Autotaxin and lysophosphatidic acid1 receptor-mediated demyelination of dorsal root fibers by sciatic nerve injury and intrathecal lysophosphatidylcholine. Mol Pain 6:78.
130. Inoue A, Arima N, Ishiguro J, Prestwich GD, Arai H, Aoki J. 2011. LPA-producing enzyme PA-PLA1α regulates hair follicle development by modulating EGFR signalling. EMBO J 30:4248–4260.
