Download Glutamate signaling in peripheral tissues

Eur. J. Biochem. 271, 1–13 (2004) FEBS 2003
doi:10.1046/j.1432-1033.2003.03907.x
REVIEW ARTICLE
Glutamate signaling in peripheral tissues
Eiichi Hinoi, Takeshi Takarada, Taichi Ueshima, Yuriko Tsuchihashi and Yukio Yoneda
Laboratory of Molecular Pharmacology, Kanazawa University Graduate School of Natural Science and Technology, Kanazawa,
Ishikawa, Japan
The hypothesis that L-glutamate (Glu) is an excitatory
amino acid neurotransmitter in the mammalian central
nervous system is now gaining more support after the successful cloning of a number of genes coding for the signaling
machinery required for this neurocrine at synapses in the
brain. These include Glu receptors (signal detection), Glu
transporters (signal termination) and vesicular Glu transporters (signal output through exocytotic release). Relatively
little attention has been paid to the functional expression
of these molecules required for Glu signaling in peripheral
neuronal and non-neuronal tissues; however, recent
molecular biological analyses show a novel function for Glu
as an extracellular signal mediator in the autocrine and/or
paracrine system. Emerging evidence suggests that Glu
could play a dual role in mechanisms underlying the maintenance of cellular homeostasis – as an excitatory neurotransmitter in the central neurocrine system and an
extracellular signal mediator in peripheral autocrine and/or
paracrine tissues. In this review, the possible Glu signaling
methods are outlined in specific peripheral tissues including
bone, testis, pancreas, and the adrenal, pituitary and pineal
glands.
Glutamate signaling molecules
lular second messengers [4,5]. The group I subtype
stimulates formation of inositol 1,4,5-triphosphate and
diacylglycerol, while both group II and III subtypes
induce reduction of intracellular cyclic AMP (cAMP). On
the basis of sequence homology and agonist preference,
the latter iGluRs are classified into N-methyl-D-aspartate
(NMDA),
DL-a-amino-3-hydroxy-5-methylisoxasole-4propionate (AMPA), and kainate (KA) receptors, which
are associated with ion channels permeable to particular
cations [6,7].
Glutamate receptors
L-Glutamate
(Glu) is accepted as an excitatory amino acid
neurotransmitter in the mammalian central nervous system (CNS). Receptors for Glu (GluRs) are categorized
into two major classes, metabotropic (mGluRs) and
ionotropic (iGluRs) receptors, according to their differential intracellular signal transduction mechanisms and
molecular homologies (Fig. 1) [1–3]. mGluRs are further
divided into three distinct subtypes containing seven
transmembrane domains, including group I (mGluR1
and mGluR5), group II (mGluR2 and mGluR3) and
group III (mGluR4, mGluR6, mGluR7 and mGluR8), in
line with each receptor’s exogenous agonists and intracel-
Correspondence to Yukio Yoneda, Laboratory of Molecular
Pharmacology, Kanazawa University Graduate School of Natural
Science and Technology, 13–1 Takara-machi, Kanazawa,
Ishikawa 920–0934, Japan. Tel.:/Fax: + 81 76 234 4471;
E-mail: [email protected]
Abbreviations: AP1, activator protein-1; AMPA, DL-a-amino-3-hydroxy-5-methylisoxasole-4-propionate; Asp, aspartate; CBFA1, core
binding factor a)1 ; CNS, central nervous system; EAAC1, excitatory
amino acid carrier 1; EAAT, excitatory amino acid transporter;
GLAST, glutamate aspartate transporter; GLT-1, glutamate transporter-1; Glu, glutamate; GluR, glutamate receptor; iGluR, ionotropic glutamate receptor; KA, kainate; mGluR, metabotropic
glutamate receptor; MK-801, dizocilpine; NMDA, N-methylD-aspartate; t-ACPD, (+/–)-1-aminocyclopentane-trans1,3-dicarboxylic acid; VGLUT, vesicular glutamate transporter.
(Received 28 August 2003, accepted 4 November 2003)
Keywords: autocrine; glutamate; glutamate receptor;
glutamate transporter; neurotransmitter; paracrine; vesicular
glutamate transporter; peripheral tissues.
NMDA receptor channels. These channels are highly
permeable to Ca2+, with sensitivity to blockade by Mg2+
in a voltage-dependent manner [8,9]. Functional NMDA
receptor channels are comprised of heteromeric assemblies
between the essential NR1 subunit and one of four different
NR2 (A–D) subunits, in addition to one of two different
NR3 (A–B) subunits. Expression of the NR2 subunit alone
does not lead to composition of functional ion channels in
any expression system, while coexpression of each NR2
subunit with an NR1 subunit results in expression of
functional channels permeable to Ca2+ in mammalian cells
[10]. In contrast, NR3 subunits are a dominant-negative
family that suppresses opening of functional NMDA
receptor channels [11–13].
AMPA/KA receptor channels. AMPA receptor channels
consist of different subunits (GluR1–4), whereas KA
receptor channels are constructed using combinations of
GluR5–7 subunits. Both KA1 and KA2 subunits are
thought to participate in the expression of functional, high
affinity KA receptor channels along with other KA receptor
subunits [7]. GluR d subunits are cloned by homology
screening and classified as iGluRs on the basis of sequence
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2 E. Hinoi et al. (Eur. J. Biochem. 271)
Table 1. Classification of glutamate transporters and vesicular glutamate transporters. Glu transporters are classified into five different subtypes including GLAST (EAAT1), GLT-1 (EAAT2), EAAC1
(EAAT3), EAAT4 and EAAT5, which are responsible for the termination of signal transduction mediated by Glu and for the prevention of neurotoxicity mediated by this endogenous excitotoxin.
Vesicular Glu transports are divided into three groups, VGLUT1,
VGLUT2 and VGLUT3. Expression of VGLUT suffices for definition
of a glutamatergic phenotype in neurons.
Transporter
Fig. 1. Classification of glutamate receptors. GluRs are divided into
two major classes, metabotropic (mGluRs) and ionotropic (iGluRs)
receptors, according to their differential intracellular signal transduction mechanisms as well as sequence homologies. There are three
distinct subtypes of mGluRs, including groups I, II and III, classified
based on sensitivity to exogenous agonists and intracellular second
messengers employed. iGluRs are subclassified, on the basis of
sequence homologies and agonist preference, into NMDA, AMPA
and KA receptors, which are all associated with ion channels permeable to particular cations.
similarity. Using different pharmacological analyses and
expression in transfected cells [14,15] researchers believe that
these d subunits are thought to be orphan receptors. In the
CNS, these iGluR and mGluRs are thought to mediate
excitatory neurotransmission and to play key roles in
synaptogenesis, formation of neuronal circuitry and to be
involved in mechanisms for synaptic plasticity such as
learning and memory [16,17]. Excessive activation of GluRs
is thought to participate in the neurodegeneration following
a wide range of neurological insults including ischemia,
trauma, hypoglycemia and epileptic seizures. Chronic
neurodegenerative disorders such as Alzheimer’s disease,
Huntington’s chorea, AIDS encephalopathy and
amyotrophic lateral sclerosis may also involve neuronal
cell death induced by Glu [18–20].
Amino acid
length (aa)
Glutamate transporters subtype
GLAST
543
GLT-1
576
EAAC1
524
EAAT4
EAAT5
564
560
Tissue
distribution
Brain, retina, testis, bone
Brain, retina, liver
Brain, intestine, kidney,
retina, liver, heart
Brain, placenta
Retina, liver
Vesicular glutamate transporter subtypes
VGLUT1
560
Brain, bone
VGLUT2
558
Brain, pancreas,
pineal gland
VGLUT3
589
Brain, retina, liver
extracellular Glu released from neurons. In astrocytes,
extracellular Glu is incorporated and converted into glutamine by glutamine synthetase, and glutamine is shuttled
back to neurons for the resynthesis of Glu in neurons [30].
On this astrocyte/neuron, glutamate/glutamine hypothesis
for the neurotransmitter compartment, astrocytes play an
important role in mechanisms underlying the disposition of
Glu at synaptic vesicles through vesicular transporters and
the recycling of Glu for exocytotic release. EAAC1 is
localized to neurons throughout the CNS [31], whereas
EAAT4 localization is largely restricted to cerebellar
Purkinje cells [27]. EAAT5 has been shown to exclusively
reside in the retina [28] and more specifically on photoreceptor and bipolar rod and cone cells [32].
Vesicular glutamate transporters
Glutamate transporters in the plasma membrane
In the CNS, Glu transporters are essential for the termination of signal transduction mediated by Glu as well as for
the prevention of neurotoxicity mediated by this endogenous excitotoxin. These transporters maintain a 10 000fold gradient of intracellular Glu (3–10 mM) to extracellular
Glu (0.3–1 lM), which is driven by the ionic gradients
generated by ion-exchanging pumps such as Na+/K+ATPase [21,22]. These Glu transporters are classified into
five different subtypes including glutamate aspartate transporter (GLAST) (EAAT1; excitatory amino acid transporter 1) [23,24], glutamate transporter-1 (GLT-1) (EAAT2)
[25], excitatory amino acid carrier (EAAC1) (EAAT3) [26],
EAAT4 [27], and EAAT5 [28] to date (Table 1). These Glu
transporters display heterologous regional and cellular
expression profiles. Both GLAST and GLT-1 are localized
to astrocytes, with GLAST predominating in the cerebellum
and GLT-1 in the cortex and forebrain, respectively [29].
These transporters are believed to sequester the majority of
The proteins responsible for vesicular glutamate transport
have only recently been identified when it was recognized
that putative inorganic phosphate transporters mediate
Glu transport for condensation reactions in synaptic
vesicles (Table 1). Within the CNS, vesicular glutamate
transporter (VGLUT) isoforms-1 [33,34] and -2 [35,36]
appear restricted to known glutamatergic neurons and
exhibit a striking complementary pattern of expression at
excitatory synapses [37,38], suggesting that they might
define the excitatory neuronal phenotype. Indeed, heterologous expression of VGLUT1 or VGLUT2 suffices to
convert inhibitory neurons to excitatory ones [34,39,40].
The expression of VGLUT1 and VGLUT2 would
account for the exocytotic release of Glu in all known
glutamatergic neurons, while VGLUT3 is expressed in a
number of cell types suggested previously to release Glu
through exocytosis, among them, dopaminergic, GABAergic and serotonergic neurons and astrocytes [41,42].
These previous findings give support to the hypothesis
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Glutamate signaling in peripheral tissues (Eur. J. Biochem. 271) 3
Fig. 2. Glutamate signaling in bone. Two distinct cell types are known to coordinate to
regulate bone formation and maintenance of
bone; bone-forming osteoblast and boneresorbing osteoclasts. Particular functional
GluRs are identified in osteoblasts (NMDA
receptors, AMPA receptors and mGluRs) as
well as in osteoclasts (NMDA receptors).
GLAST sensitive to mechanical stress is
expressed in both osteoblasts and osteocytes,
while VGLUTs are responsible for Glu release
from intracellular vesicular constituents
through activation of particular iGluR subtypes present in osteoblasts.
that expression of either VGLUT would suffice for the
definition of a glutamatergic phenotype in endocrine cells
[43,44] as also shown in neurons [33,34].
Glutamate signaling in peripheral tissues
Relatively little attention has been paid to functional
expression of Glu signaling molecules in peripheral tissues.
Evidence is emerging for a role of Glu as an extracellular
signal mediator in the autocrine and/or paracrine system, in
addition to an excitatory amino acid neurotransmitter role
in the CNS [45]. We have shown previously that specific
binding sites of [3H]Glu are localized with high affinity,
selectivity and quisqualate sensitivity in rat adrenal [46] and
pituitary [47] glands, in addition to the brain. Quisqualatesensitive, Cl–/Ca2+-dependent [3H]Glu binding is also seen
in bovine pineal membranes [48]. Both NMDA and L-Glu
induce a rapid contraction of the guinea pig ileum in a
manner sensitive to NMDA antagonists [49–51]. Contraction is also induced by Glu in rat bronchial smooth muscle
with pharmacological profiles different from those for any
known GluRs in the brain [52]. In addition to these
pioneering previous studies, recent molecular biological
analyses give support to the expression of particular Glu
signaling molecules in a variety of different neuronal and
non-neuronal peripheral locations. These include bone
(osteocyte, osteoblast, and osteoclast) [53–55], testis
[56,57], pancreas [44,58,59], adrenal gland [60,61], pituitary
gland [62,63], pineal gland [64,65], taste buds [66], lung [67],
hepatocyte [68], thymus [69], cerebral endothelium [70],
megakaryocytes [71], keratinocytes [72], lymphocytes [73],
platelets [74], and heart [75]. In this article, we focus on Glu
signaling machinery expressed in particular tissues.
Bone
Two distinct cell types are known to coordinate to regulate
bone formation and maintenance, these are bone-forming
osteoblast and bone-resorbing osteoclasts. An imbalance
between these cells leads to pathogenesis and to etiologies of
certain metabolic bone diseases including osteoporosis,
Paget’s disease, and osteopetrosis [76,77]. The balancing
mechanism, at least in part, involves endocrine control (via
estrogen and parathyroid hormone) and paracrine (autocrine) control (via interleukin, insulin-like growth factor and
fibroblast growth factor) [76,77]. Recent studies have raised
the possibility that Glu may be one of the endogenous
paracrine (autocrine) factors used for intercellular communications in bone cells [53,54] (Fig. 2).
In mammalian bone, NMDA receptors are also expressed
in osteoblasts and osteoclasts as revealed by RT-PCR, in situ
hybridization, immunohistochemistry, and electrophysiology [54,55,78–81]. Further studies reveal the expression of
functional NMDA receptor channels in osteoblasts and
osteoclasts. The addition of an NMDA receptor antagonist
inhibits cell differentiation in cultured osteoclasts [55,82],
while Glu induces elevation of intracellular free Ca2+ in a
manner sensitive to antagonism by the NMDA receptor
antagonist, dizocilpine (MK-801) in the human osteoblastic
cell lines MG63 and SaOS-2 [83]. In our hands, however,
expression of mRNA was seen for GLT-1 and EAAT4, but
not for either other Glu transporters or any GluR subtypes
including NMDA receptors, in mouse primary cultured
osteoclasts differentiated from monocyte/macrophage progenitor cells purified by Ficoll density gradient centrifugation
(E. Hinoi, T. Takarada, M. Inoue and Y. Yoneda, unpublished data).
In addition to NMDA receptors, osteoblasts constitutively express mRNA for non-NMDA receptors such as the
GluR3 subunit of AMPA receptors and KA1 and KA2
subunits of KA receptors [84]. AMPA receptors modulate
the exocytotic release of Glu from cultured osteoblasts
[85,86]. An antagonist for AMPA receptors is shown to
significantly inhibit the release of endogenous Glu in a
concentration-dependent manner in MG-63 osteosarcoma
cells [85], whereas AMPA facilitates the release of endogenous Glu from cultured osteoblasts in the presence of the
inhibitor of AMPA receptor desensitization cyclothiazide
[86]. Moreover, constitutive expression is also shown for
particular mGluR (mGluR4 and mGluR8) that are coupled
negatively to adenylyl cyclase thus inhibiting the formation
of cAMP stimulated by forskolin in cultured rat calvarial
osteoblasts during different developmental states [79], and
prior stimulation of mGluR by (+/–)-1-aminocyclopentane-trans-1,3-dicarboxylic acid (t-ACPD) leads to reduction of NMDA-induced whole cell current in cultured rat
femoral osteoblasts [87]. Of the EAAT subtypes cloned to
date, both GLAST and GLT-1 are shown to reside in bone
with respect to mRNA and corresponding proteins, without
expression of immunoreactive EAAC1 [53,88]. Mechanical
4 E. Hinoi et al. (Eur. J. Biochem. 271)
loading is shown to down-regulate GLAST expressed in
osteocytes when determined by immunohistochemistry [53].
In GLAST knockout mice, however, no marked differences
are seen in a variety of phenotypes including mandible
and long bone size, morphology, trabeculation, regions of
muscle attachment, resorption lacunae, and areas of
formation vs. resorption of bone, compared with wild-type
siblings [89]. In addition to Glu transporters expressed at the
cell surface, both RT-PCR and immunohistochemical
analyses reveal constitutive expression of membrane and
intracellular molecular machinery generally required for
vesicular release of a central neurotransmitter in osteoblastic
cell lines as well as primary cultured osteoblasts [90]. We
have also demonstrated constitutive expression of particular
VGLUT in cultured osteoblasts irrespective of maturity of
cultured osteoblasts [86].
Core binding factor a)1 (CBFA1) is a transcription factor
essential for the growth of osteoblasts and is a master
regulator at the differentiation stage [91,92]. Disruption of
CBFA1 prevents skeltogenesis and heterozygous mutations
lead to cleidocranial dysplasia, an autosomal dominant
disorder [93,94]. CBFA1 is also shown to regulate expression
of several genes such as collagenase-3, type (I) collagen,
osteoprotegerin, bone sialoprotein, osteopontin, and alkaline
phosphatase in addition to osteocalcin [95–97]. We have also
recently demonstrated the exacerbation of osteoblastic
differentiation by different NMDA receptor antagonists
[55]. Sustained exposure to MK-801 invariably leads to
marked inhibition of expression of both mRNA and
corresponding protein for the master regulator of bone
differentiation CBFA1 (in addition to its DNA binding
activity) in primary cultured rat calvarial osteoblasts when
determined after the stage of cellular differentiation [55]. The
antagonist not only inhibits temporal marked expression of
CBFA1 seen at the stage of cell differentiation but also
prevents Ca2+ accumulation only when added before the
period of cell differentiation. The lack of effects of
MK-801 on Ca2+ accumulation and cell numbers throughout cell growth, when added after the stage of cell differentiation, gives support to the proposal that NMDA receptors
predominantly modulate cell differentiation rather than
proliferation through a mechanism associated with expression of CBFA1 during cellular maturation in osteoblasts.
As mentioned above, bone cells could express all molecular machinery required for Glu signaling in the CNS. Glu
signals in bone, as seen at glutamatergic synapses in the brain,
could be dispatched through exocytotic release from vesicles
expressing VGLUT for condensation in vesicular particles,
transduced specifically via both iGluRs and mGluRs and
terminated by Glu transporters. Moreover, bone is supposed
to have sympathetic and glutamatergic innervations
[98–100]. Accordingly, Glu could have a pivotal dual role
in mechanisms associated with maintenance of homeostasis
as an excitatory neurotransmitter (toward neurocrine processes in the CNS) and as a trophic factor (toward autocrine
and/or paracrine processes in bone).
Testis
A testis consists of seminiferous tubules and interstitial cells,
specifically Leydig cells, having unique functions in the male
body – the generation of gametes and the production and
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controlled release of sex steroids [101–103]. The seminiferous tubules include germ cells as well as somatic cells such as
Sertoli cells. Spermatogenesis in mammals is characterized
by intense and continuous proliferative activity with a
complex pattern of mitotic divisions in different types of
spermatogonia, culminating in meiotic cleavage of primary
spermatocytes to produce noncycling haploid cells (spermatids). Development of male germ cells in the seminiferous
tubules is dependent on the action of pituitary gonandotropins and androgens secreted from Leydig cells. The entire
process of germ cell development, moreover, also relies on
Sertoli cells for structural and nutritional support. For
instance, germ cells are segregated from the systemic
circulation because of the blood–testis barrier created by
tight junctions between Sertoli cells near the basal lamina
[104,105] as seen with astroglial cells for the blood–brain
barrier.
In rat testis tissue, mRNA and corresponding proteins
are constitutively and functionally expressed for both
mGluR1 and mGluR5, but not for mGluR2 and mGluR3
[56]. Immunohistochemical and molecular biological analyses reveal the expression of NR1, GluR2/3, and mGlu
R2/3 proteins in kidney, liver, lung, spleen, and testis
[106,107]. In addition to functional expression of GluRs,
Glu transporters are also expressed in testis tissue. A
Northern blot study showed expression of mRNA for a
novel Glu transporter later found to be identical to
GLAST [22,23] in rat forebrain, cerebellum, and testis
[108]. Expression of mRNA is also shown for a neuronspecific Glu transporter (later identified as EAAC1)
isolated from human brain cDNA libraries in human
brain, liver, muscle, ovary and testis using Northern blot
analysis [109]. Figure 4 shows our recent findings on the
distribution profiles of different Glu transporters expressed
in rat testis. In Fig. 3A, a schematic representation is
shown for histological characteristics of testis tissue. In
these experiments, rat testes were removed and frozen
sections dissected with subsequent fixation with paraformaldehyde for detection of localization of each mRNA
using DIG-labeled cRNA probe. In situ hybridization
evaluation demonstrated clearly the localized expression of
mRNA for GLAST in the interstitial space of rat testis
(Fig. 3b). Constitutive expression is seen with mRNA for
GLT-1 in elongated spermatids of rat testis, while expression of EAAT5 mRNA is found in the basal compartment
of seminiferous tubule in rat testis. However, mRNA
expression is not seen for EAAC1 and EAAT4 in any
particular structures of rat testis.
D-Aspartate (D-Asp) endogenously occurs in rat adenohypophysis, testis, adrenal gland, and brain in a rank order
of decreasing levels, while an intraperitoneal injection of
exogenous D-Asp induced a marked increase in its accumulation in these neuroendocrine tissues [110]. Exposure of
cultured rat Leydig cells to D-Asp selectively stimulates
testosterone synthesis after its incorporation into cells
through GLAST but exposure to L- and D-Glu, L-Asp
and L- and D-aspargine is ineffective [57]. The prevailing
view, that all Glu transporters cloned to date are unable to
differentiate between L- and D-Asp as a substrate, argues in
favor of a role for endogenous D-Asp in testosterone
synthesis following incorporation through particular Glu
transporters expressed at surfaces of Leydig cells.
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Glutamate signaling in peripheral tissues (Eur. J. Biochem. 271) 5
Fig. 3. Analyses on localization of Glu transporters in rat testis. (A) Schematic representation of the histological characteristics of
testis. (B) Rat testicular frozen sections were
fixed with paraformaldehyde and then incubated with DIG-labeled cRNA probe for
GLAST, GLT-1, EAAC1, EAAT4 and
EAAT5 for in situ hybridization. Typical
micrographs are shown in the figures with
similar results in three independent experiments. Scale bars, 50 lm.
Pancreas
The islet of Langerhans, a pancreatic miniature organ for
several hormones regulating the blood glucose level, is
composed of four major types of endocrine cells, including
glucagon-secreting alpha (a) cells, insulin-secreting beta (b)
cells, somatostatin-secreting d cells, and pancreatic polypeptide-secreting F cells. The B cells are the most numerous
and are concentrated in the center of the islet, while the
a cells are larger and less numerous and located at the
periphery of the islet [111,112].
By molecular biological, electrophysiological, and
immunohistochemical studies, it has been reported that
these islet cells should express functional Glu receptors
[58,59,113–119], Glu transporters [120,121] and VGLUT
[43,44,122], suggesting that Glu could function as an
intercellular signal mediator in the islet (Fig. 4). Several
independent lines of evidence indicate that iGluR stimulation positively modulates secretion of both glucagon and
insulin in pancreatic islets. Insulin secretion is stimulated
by AMPA, KA and NMDA in MIN6 cells derived from
insulin-secreting pancreatic b cells [58], and also induced
by both AMPA and KA, but not by NMDA, in isolated
pancreatic islets [113,123]. Similarly, Glu stimulates glucagon secretion via AMPA receptors in rat isolated
pancreatic islets [124]. It has been demonstrated that
mGluRs also participate in hormone secretion from
pancreatic islets. Agonists for group I and II mGluR
subtypes increase the release of insulin in the presence of
glucose at low concentrations, whereas a group III
mGluR agonist inhibits insulin release determined at high
glucose concentrations [119]. The activation of group III
mGluR subtype expressed in pancreatic a cells leads to
inhibition of glucagon release [59]. A high-affinity Glu
transporter expressed in pancreatic islets of Langerhans
modulates insulin secretion stimulated by glucose [121].
Besides expression in neuronal cells, moreover, both
VGLUT1 and VGLUT2 are expressed preferentially in
aTC6 cells, clonal pancreatic a cells, as well as a cells
isolated from Langerhans islets [43,44]. Low glucose
conditions result in cosecretion of stoichiometric amounts
of Glu and glucagon from aTC6 cells and isolated islets,
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6 E. Hinoi et al. (Eur. J. Biochem. 271)
Fig. 4. Glutamate signaling in pancreas. The islet of Langerhans, a
pancreatic miniature organ, is composed of four major types of
endocrine cells, including a, b, d and F cells. Particular functional
GluRs, which could modulate secretion of hormones, are identified in
a cells (AMPA receptors, KA receptors and mGluRs), in b cells
(AMPA receptors), and in d cells (KA receptors), respectively. Highaffinity Glu transporters are expressed in both a and d cells, while
VGLUTs are preferentially expressed in a cells.
which triggers GABA secretion from B cells through
GluRs in the isolated islets [44].
Adrenal gland
Adrenal gland consists of two concentric layers; adrenal
cortex which is a yellow peripheral layer, and adrenal
medulla which is a reddish-brown central layer. Adrenal
cortex has the characteristics of steroid-synthesizing tissues,
with subdivision into the three concentric layers – the zona
glomerulosa, the zona fasciculate and the zona reticularis.
The zona glomerulosa secrets mineralocorticoids such as
aldosterone (involved in the maintenance of balance
between electrolytes and water), while the zona fasciculata
and probably the zona reticularis secret the glucocorticoids
corticosterone and cortisol (both relevant to the regulation
of metabolism of carbohydrates, proteins, and fats).
Adrenal medulla is composed of polyhedral parenchymal
cells and supported by a reticular fiber network, and secretes
both adrenaline and noradrenaline [125,126].
The role of Glu in adrenal glands has been investigated in
independent research laboratories including ours. In addition to Glu [127], iGluR agonists (NMDA, AMPA and
KA) and an mGluR agonist (t-ACPD) [128] all stimulate
catecholamine release from adrenal glands. We have shown
previously the localization of [3H]Glu binding sites with
stereoselectivity, high affinity and saturability in rat adrenal
medulla [46,129]. Adrenal [3H]Glu binding sites are solubilized by detergents with pharmacological profiles similar to
those found in membrane preparations [130,131]. On
sections of rat [132] and bovine [133] adrenal glands,
[3H]Glu binding sites are of high affinity, rapid, saturable,
reversible, stereospecific, and specific to a single population.
In addition to these early studies using conventional
techniques, recent molecular biological analyses support
the presence of particular iGluR subunits in adrenal glands.
Rat adrenal cortex expresses AMPA receptors [134], but
adrenal medulla expresses NMDA receptors [135] as
revealed by in situ hybridization. We could also detect both
mRNA and corresponding proteins for NR1, NR2C and
NR2D in rat adrenal medulla [61]. Furthermore, an
intraperitoneal injection of a blocker of NMDA receptor
channels, but not NMDA itself, leads to a marked increase
in DNA binding activity of the nuclear transcription factor
AP-1 in rat adrenal glands [61]. Single episodes of immobilization stress induces a significant increase in NR1
mRNA expression in adrenal glands [136], while a single
dose of morphine decreases NR1 mRNA in adrenal glands
but not in hippocampus [137]. The prior systemic administration of NMDA prevents the marked increase in adrenal
AP1 DNA binding induced by subsequent stress [138]. In
rat adrenal glands, the expression of GLAST, which has an
affinity for D-Asp, is transiently increased at 3 weeks of age
[139] and localization patterns are almost coincident with
those of endogenous D-Asp within the glands. Adrenal
glands receive sympathetic efferent and afferent innervations in addition to the typical cholinergic innervation
[140,141]. A mechanism for Glu release is detected in bovine
adrenal chromaffin cells [142] and glutamatergic innervation
is also found in sympathoadrenal neurons [143,144].
Pituitary gland
The pituitary gland is connected to the hypothalamus at the
base of the brain and consequentially important anatomical
and functional relationships exist. During embryogenesis,
the pituitary gland develops from the oral ectoderm and
also nerve tissue. The pituitary tissue from nerve tissue is
referred to as the neurohypophysis and consists of the pars
nervosa and infundibulum, while the pituitary gland derived
from oral ectoderm is known as the adenohypophysis and
has three different areas – the pars distalis or anterior lobe,
the pars tuberalis and the pars intermedia [145,146]. A
portion of the pars intermedia is sometimes included in the
terminology Ôposterior lobeÕ.
Molecular biological and immunohistochemical analyses
demonstrated the presence of both non-NMDA [62,147,
148] and NMDA receptors [149,150], while studies using
autoradiographic [151] and receptor binding [47,152] techniques showed the localization of [3H]Glu binding in the
pituitary gland. Several independent lines of evidence for
direct regulation by Glu of hormone secretion in isolated
anterior pituitary cells are available in the literature. The
secretion of prolactin is stimulated by Glu in a manner
sensitive to prevention by MK-801 in primary cultures of
anterior pituitary cells [153,154]. Both NMDA and KA
facilitate the secretion of growth hormone in dispersed
anterior pituitary cells [155], while KA is effective in
stimulating gonandotropin secretion from the anterior
pituitary [156]. In single primary cultured rat anterior
pituitary cells, Glu induces a marked increase in cytosolic
free Ca2+ concentration by a nonsynaptic mechanism [157].
These previous findings show functional expression of
particular subtypes of GluRs in the pituitary gland. We
have also demonstrated that the rat pituitary gland contains
both mRNA and corresponding proteins for GluR6/7
subunits of KA receptors in addition to specific binding sites
of [3H]KA [63]. Moreover, an intraperitoneal injection of
KA results in increased AP1 DNA binding in rat pituitary
gland as well as hippocampus [63].
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Pineal gland
Mammalian pineal gland consists of several types of cells,
principally pinealocytes and astroglial cells. Pinealocytes
are endocrine cells with the ability to synthesize and secret
melatonin, a hydrophobic hormone that mediates many
physiological functions such as circadian rhythms and
seasonal reproduction [158,159].
[3H]Glu binding is also seen in bovine [48] and rat
[160] pineal membranes. Exogenous Glu leads to inhibition
of the activities of serotonin N-acetyltransferase [161] and
hydroxyindole O-methyltransferase [162], with concomitant suppression of both synthesis and secretion of melatonin [163,164]. Furthermore, expression of particular
GluRs has been confirmed in the mammalian pineal gland
in molecular biological and immunohistochemical studies
to date. These include GluR delta [165], AMPA [166], KA
[167], NMDA [167], group I mGluR [168,169], and group
II mGluR [64,169]. Activation of mGluR3 negatively
regulates noradrenaline-dependent serotonin N-acetyltransferase activity and melatonin synthesis in rat pinealocytes [64], while GluR1 triggers exocytosis mediated by
microvesicles (counterparts of the neuronal synaptic vesicles) of Glu through activation of L-type Ca2+ channels in
rat pinealocytes [65]. Immunoreactive Glu is enriched in
pinealocytes of gerbil pineal gland [170], and pinealocytes
accumulate Glu in microvesicles [171] for secretion through
Ca2+-dependent exocytosis [172–174]. In mammalian
pinealocytes, expression of VGLUT2 is confirmed in
addition to expression in Langerhans islets [43]. Extracellular Glu is sequestered by pinealocytes through a GLT-1
type, Na+-dependent Glu transporter expressed in the
plasma membrane [175], whilst immunoreactivity to
GLAST is detected in interstitial glial cells but not in
pinealocytes [176].
Other tissues
In rat hepatocytes, the mGluR agonists, t-ACPD and
quisqualate, not only stimulate polyphosphoinositide
hydrolysis, with an antagonist for group I mGluR subtype
protecting against hypoxic damage [68]. Constitutive
expression of particular iGluRs, including NR1, NR2D,
KA2, and GluR delta-1 subunits [177], is found in lingual
epithelium obtained from rat foliate and vallate papillae, in
addition to truncated a variant of mGluR4a [66,178]. These
GluRs may be responsible for sensory transduction of
ÔumamiÕ taste in addition to the taste-specific receptor,
T1R1/T1R3 dimer, which is coupled to G-protein for
activation by dietary Glu [179]. The expression of both
group I and group II mGluRs is demonstrated in mouse
thymus, isolated thymocytes and thymic stromal cell line
[69]. The quisqualate-sensitive binding of [3H]Glu is detected
in T lymphocytes [180], whereas in human lymphocytes,
Glu and other iGluR agonists potentiate the rise of
intracellular free Ca2+ concentrations induced by the
mAb anti-CD(3) or phytohaemagglutinin [73]. In human
platelets, Glu or NMDA is antagonistic for the aggregating
activity of arachidonic acid, with detection of both
NMDA-displaceable [3H]Glu binding and [3H]MK-801
binding [74,181]. In megakaryocytes, both mRNA and
proteins for NMDA receptors are expressed in addition to
autoradiographic binding of [3H]MK-801. Blockade of
NMDA receptors, by specific antagonists, inhibits the
phorbol myristate acetate-induced increases in cellular size,
CD41 expression and mutual adhesion in MEG-01 clonal
megakaryoblastic cells [71]. Both NMDA and non-NMDA
receptors are expressed in rat heart [75], while the stimulation of iGluRs by Glu, NMDA, AMPA and KA invariably
leads to an increase in intracellular Ca2+ oscillation
frequency in cultured rat myocardial cells [182]. Moreover,
mGluRs (mGluR1, mGluR2/3, and mGluR5) are also
expressed in rat heart [183]. Expression of NMDA receptors
has been demonstrated in lung [184,185] and NMDA elicits
acute high-permeability edema in perfused rat lungs [67].
Nitric oxide synthase inhibitors and the neuropeptide
vasoactive intestinal peptide protect against injuries mediated by NMDA receptors in lung [186]. In whole guinea-pig
lungs perfused via the trachea, NMDA increases airway
perfusion pressure in a manner that is totally abolished by
MK-801 [187]. Expression of particular GluRs is shown in
skin including keratinocytes for NMDA and AMPA
receptors [72,188] and melanocytes for mGluR5 [189].
Blockade of NMDA receptors expressed in keratinocytes,
induces stratification and other characteristics of differentiation [72]. Another excitatory amino acid, L-Asp, inhibits
acid secretion stimulated by histamine, without affecting
that by oxotremorine and pentagastrin in an everted
preparation of isolated rat stomach [190], while an NMDA
receptor antagonist blocks the inhibitory effect of L-Asp on
histamine-stimulated acid secretion [190].
Conclusions
It appears that the molecular machinery required for Glu
signaling, which includes iGluRs, mGluRs, Glu transporters and VGLUTs, are constitutively expressed to play a role
crucial for maintenance of the functionality and integrity
in several neuronal and non-neuronal peripheral tissues
(Table 2). Circulating Glu seems to be sufficient for
saturation of any of the subtype of iGluRs and mGluRs
expressed at peripheral locations with intimate contacts to
the blood supply. One possibility is that peripheral GluRs
could be under the influence of tonic stimulation by Glu in
plasma, whereas an alternative explanation is that circulating Glu may not easily gain access to peripheral GluRs due
to particular protection mechanisms against the direct
exposure to blood supply. From this point of view, the exact
origin of an endogenous agonist is still unclear in contrast to
the conclusive evidence for expression of mRNA for
particular iGluR and mGluR subtypes as well as for
VGLUTs in peripheral tissues.
In any case, Glu seems to play a dual role in mechanisms
underlying maintenance of homeostasis – an excitatory
neurotransmitter in the central neurocrine system and an
extracellular signal mediator in the peripheral autocrine
and/or paracrine process. Searches for ligands at GluRs and
Glu transporters may need to be rerun with regard to
permeability to the brain across blood–brain barrier.
Nonpermeable compounds could be of a great benefit as
therapeutic drugs without serious central side-effects for a
variety of disorders associated with malfunction of Glu
signaling in the periphery. In contrast to the prevailing view,
a new concept could be required for classification of
FEBS 2003
8 E. Hinoi et al. (Eur. J. Biochem. 271)
Table 2. Expression of Glu signaling molecules in several neuronal and
non-neuronal peripheral tissues. iGluR (A, AMPA receptors; K, KA
receptors; N, NMDA receptors); mGluR (I, group I mGluR; II, group
II mGluR; III, group III mGluR); GluT (1, GLAST; 2, GLT-1; 3,
EAAC1; 4, EAAT4; 5, EAAT5); VGLUT (1, VGLUT1; 2, VGLUT2;
3, VGLUT3). ND, not determined; ?, unidentified.
Tissue/cell
iGluR
mGluR
GluT
VGLUT
Osteoblast
Osteoclast
Osteocyte
Testis
Pancreas
Adrenal gland
Pituitary gland
Pineal gland
Hepatocyte
Lingual
epithelium
Thymus
T lymphocyte
Platelet
Megakaryocyte
Heart
Lung
Keratinocyte
Melanocyte
+ (A,K,N)
+ (N)
ND
+ (A,K,N)
+ (A,K,N)
+ (A,K,N)
+ (A,K,N)
+ (A,K,N)
ND
+ (K,N)
+ (I, II)
ND
ND
+ (I, II)
+ (I, II, III)
?
ND
+ (I, II)
+ (I)
+ (III)
+ (1)
ND
+ (1)
+ (1,2,5)
+ (2)
+ (1)
ND
+ (1,2)
ND
ND
+ (1)
ND
ND
ND
+ (1,2)
ND
ND
+ (2)
ND
ND
ND
?
?
+ (N)
+ (A,K,N)
+ (N)
+ (A,N)
ND
+ (I, II)
ND
ND
ND
+ (I, II)
ND
ND
+ (I)
ND
ND
ND
ND
+ (1,3)
ND
+ (2,3)
ND
ND
ND
ND
ND
ND
ND
ND
ND
extracellular signal mediators between different cells for
neurocrine, endocrine, autocrine, and paracrine communications.
Acknowledgements
This work was supported in part by Grants-in-Aids for Scientific
Research to E.H. and Y.Y. from the Ministry of Education, Culture,
Sports, Science and Technology, and to Y.Y. from the Ministry of
Health, Labour and Welfare, Japan, respectively.
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