Endocrinology and Reproduction Research Branch, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland 20892
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ABSTRACT |
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Inositol lipid kinases
generate polyphosphoinositides, important regulators of several
cellular functions. We have recently cloned two distinct
phosphatidylinositol (PI) 4-kinase enzymes, the 210-kDa PI4KIII and
the 110-kDa PI4KIII
, from bovine tissues. In the present study, the
distribution of mRNAs encoding these two enzymes was analyzed by in
situ hybridization histochemistry in the rat. PI4KIII
was found
predominantly expressed in the brain, with low expression in peripheral
tissues. PI4KIII
was more uniformly expressed being also present in
various peripheral tissues. Within the brain, PI4KIII
showed highest
expression in the gray matter, especially in neurons of the olfactory
bulb and the hippocampus, but also gave a signal in the white matter indicating its presence in glia. PI4KIII
was highly expressed in
neurons, but lacked a signal in the white matter and the choroid plexus. Both enzymes showed expression in the pigment layer and nuclear
layers as well as in the ganglion cells of the retina. In a 17-day-old
rat fetus, PI4KIII
was found to be more widely distributed and
PI4KIII
was primarily expressed in neurons. These results indicate
that PI4KIII
is more widely expressed than PI4KIII
, and that the
two enzymes are probably coexpressed in many neurons. Such expression
pattern and the conservation of these two proteins during evolution
suggest their nonredundant functions in mammalian cells.
inositol lipids; calcium; phospholipase C; wortmannin
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INTRODUCTION |
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INOSITOL PHOSPHOLIPIDS have been recognized as important regulators of a variety of cellular functions. The best characterized of their regulatory roles is the receptor-mediated production of the second messengers, D-myo-inositol 1,4,5-trisphosphate [Ins(1,4,5)P3] and diacylglycerol, by phospholipase C (PLC)-mediated hydrolysis of membrane phosphatidylinositol-4,5-bisphosphate [PtdIns(4,5)P2] (4). More recently, it has become evident that PtdIns(4,5)P2 and its 3-phosphorylated product, PtdIns(3,4,5)P3, may have additional regulatory roles by controlling the assembly and activities of several protein-signaling complexes at specific membrane compartments (35). This latter aspect of inositol lipid-based signaling makes use of the various forms of inositol lipid kinase and phosphatase enzymes that have been described in recent years (12).
Phosphatidylinositol (PI) 4-kinases are the enzymes that catalyze the
4-phosphorylation of PI, the first step in a reaction sequence that
leads to the formation of most of the polyphosphoinositides [recent evidence suggests that some 5-phosphorylation of PI may precede 4-phosphorylation (30)]. The majority of the cellular PI
4-kinase activity is represented by the tightly membrane-bound type II
4-kinase, an activity that has been purified from various tissues as a
50-56-kDa protein (see Ref. 6) but still awaits molecular cloning
and characterization. In contrast, two distinct forms of the less
abundant type III phosphatidylinositol 4-kinases (PI4KIII)
have been purified from bovine adrenal (2) and brain (14) and cloned
from various species, including humans (23). These two enzymes, the
110-kDa form [called 92-kDa PI 4-kinase in the rat based on
its calculated molecular size (25)] and the 210-kDa
form
[called 230-kDa PI 4-kinase in the rat (24)] are homologues
of two yeast PI 4-kinases, products of the PIK1 and STT4 genes,
respectively (10, 39). Also, these proteins contain the characteristic
signature of the ATP-binding catalytic domain of PI 3-kinases and PI
kinase homologues (17) and are also inhibited by the microbial product,
wortmannin, the most potent inhibitor of PI 3-kinases (37).
It is an intriguing question as to why these two PI 4-kinases evolved
so early and remained highly conserved during evolution [the
homologues of both enzymes have also been cloned from plants (33,
38)]. Genetic evidence of the importance of these proteins in
yeast indicates that both proteins are essential for survival in most
strains (7, 10) and that they cannot substitute for one another's
function. In the present study, we compared the tissue distribution of
these two enzymes by in situ hybridization in the rat to obtain further
clues about their relative importance in the various tissues. Our
results show that although both enzymes are ubiquitously expressed,
there are notable differences in their tissue distribution, and that
both the smaller , and the larger
forms are most prominently
expressed in neurons.
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EXPERIMENTAL PROCEDURES |
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Riboprobes were made from PCR products that were generated with primers
in which the T3 (for the sense) and T7 (for antisense) RNA polymerase
recognition sequences were added to flank the upstream and downstream
primers, respectively. For PI4KIII, sequences from 5245-5738 of
the rat PI 4-kinase p230 were used, and for PI4KIII
, sequences from
2465-2772 of the rat PI 4-kinase p92 were used [see (1) for
nomenclature]. At these regions there was low
homology between the nucleotide sequences of the two enzymes (~50%).
Riboprobes were made from the gel-purified PCR products as templates
using 35S-labeled UTP and the respective RNA polymerase.
For in situ hybridization histochemistry, a protocol displayed on the website (http://intramural.nimh.nih.gov/lcmr/snge) was followed (19). Briefly, 12-µm tissue sections made from frozen tissue blocks obtained from male Sprague-Dawley rats (killed under CO2 anesthesia for other experimental purposes) were fixed with 4% paraformaldehyde and washed twice with RNAse-free PBS. After this treatment, the slides were subjected to 0.25% acetic anhydride (freshly made in 0.1 M triethanolamine/HCl, pH 8.0) for 10 min followed by sequential washes in increasing concentration of ethanol.
Tissue sections were hybridized in a wet chamber with the radioactive probes for 22 h at 55°C. Slides were rinsed with 4× sodium chloride-sodium phosphate-EDTA (SSPE)/1 mM 1,4-dithiothreitol (DTT) four times for 5 min at room temperature before two 30 min washes of 65°C with 0.1× SSPE/1 mM DTT. Before drying, slides were rinsed twice with 1× SSPE at room temperature. The slides were then exposed to X-ray films and subsequently coated with Kodak NTB-3 nuclear track emulsion for 1 wk exposure.
The same riboprobes were used to hybridize for Northern blot analysis of membranes containing poly(A)+-selected mRNA from various rat tissues (Clontech) using the method previously described for the human tissues (2).
For comparison of the relative amounts of the two proteins expressed in the brain, two rat brains were homogenized, and the proteins purified, on heparin and MonoQ columns as described previously (2). [3H]wortmannin binding (2) was used to quantitate the proteins from the active fractions.
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RESULTS |
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Distribution of and
forms of
PI4KIII in the rat brain.
To characterize the riboprobes chosen for in situ hybridization, we
performed Northern blot analysis with the antisense riboprobes on
poly(A)+-selected mRNA of various rat tissues. The
expression patterns and the size of the two transcripts (7.2 kb and 3.3 kb for PI4KIII
and PI4KIII
, respectively) were found to be almost
identical to those published for these two enzymes in the rat (24, 25). Because both
and
forms show relatively high expression in the
rat brain (Fig. 1), first we
studied the distribution of the transcripts in brain tissue. When a
series of coronal sections of rat forebrain were analyzed by in situ
hybridization, prominent labeling was observed with the antisense probe
of the type III
-enzyme, which was mostly confined to the gray
matter (Fig. 2, A-E).
Neurons of the cerebral cortex, as well as of the olfactory lobe and
the hypothalamus, were strongly positive (Figs. 2 and 3). No signal was detected in any of the
brain areas with the sense probes (see Fig. 2 for an example). The
strongest signal was detected in limbic areas such as the cell bodies
of pyramidal cells in the CA1-CA3 layer of the hippocampus and the
granule cells of the dentate gyrus (Fig. 2, B and C).
The amygdaloid nucleus and the entorhinal cortex also showed a very
strong signal, indicating the abundant presence of mRNA for PI4KIII
.
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PI4KIII is the predominant enzyme in the brain.
To compare the relative amounts of the two enzymes expressed in the
brain, rat brains were homogenized and the membrane fraction solubilized with cholate essentially as described by Endemann et al.
(9). The wortmannin-sensitive PI 4-kinase activity was enriched by
heparin and MonoQ chromatographies. Given the comparable affinities of
the two proteins for wortmannin (2),
[3H]wortmannin binding was used to assess the
relative quantities of the two proteins from the active fractions. As
shown in Fig. 4, the larger
-enzyme
represented the majority of the activity in the rat brain (as well as
in the bovine brain, not shown).
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Both PI4KIII and PI4KIII
are
expressed in the retina.
Next we examined whether the transcripts for these two enzymes were
detectable in the retina. As shown in Fig.
5, a strong signal was detected above the
ganglionic cells, especially with the antisense
-probe, and the
inner nuclear layer. A somewhat weaker signal was found in the pigment
epithelium and in the outer nuclear layer. The signals were generally
weaker with the
-probe than with the
-probe. Again, only a low
evenly distributed background signal was detected with either of the
sense riboprobes (Fig. 5).
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Localization of the two PI 4-kinase enzymes in peripheral tissues.
Based on Northern blot analysis, the abundance of mRNA for the form
of PI 4-kinase was generally very low but detectable in peripheral
tissues. In contrast, PI 4-kinase
was more widely expressed (Fig. 1
and Refs. 24 and 25), and, therefore, its distribution was
further examined by in situ hybridization histochemistry in peripheral
tissues. As shown in Fig. 6, PI4KIII
mRNA was detected in the kidney, especially in the papilla of the
medulla, and also in the glomeruli of the cortex. In the spleen there
was a diffuse signal both over the red and the white pulp. In the
heart, the signal was confined to the atria, the ventricles showing
very low if any expression. The testis showed a clear signal over the seminiferous tubules, but little in the interstitium. Of the other tissues tested, a weak signal was found in the liver and the stomach (not shown).
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Localization of the two PI 4-kinase enzymes in rat embryo.
The expression pattern of the two PI 4-kinase enzymes was also examined
in a midsagittal section of a 17-day-old rat embryo (Fig.
7). The form of the enzyme showed high
expression levels in the developing brain and eye, as well as in the
trigeminal ganglia. Among the peripheral tissues, a relatively strong
signal was detected in the salivary glands, the lungs, and the liver. The
form of the enzyme was again more evenly expressed, but the
brain and trigeminal ganglion showed the highest expression levels.
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DISCUSSION |
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The present study was undertaken to investigate the tissue distribution
of the two cloned type III PI 4-kinase enzymes, the and
forms,
to complement similar studies on other important protein members of the
inositide-Ca2+ signal transduction cascade (13, 18, 31).
Both of these enzymes were found to be widely expressed in the rat, but
the
form was predominantly localized to the brain in both the fetus and adult animals. Although more uniformly expressed, the
form of
the enzyme also showed highest expression in the brain. The brain still
contained mostly the
form and a relatively small amount of the
form of the enzyme when the protein amounts were compared. The brain
has long been known to contain the highest concentrations of
polyphosphoinositides (11), and both type II and type III PI 4-kinase
activities have been isolated from brain tissue (9, 14). In the present
study, both type III enzyme mRNAs showed the highest levels of
expression in the hippocampus and dentate gyrus, areas that are
generally rich in proteins involved in inositide/Ca2+
signaling. In most part, the gray matter showed a clear signal with
both riboprobes, and the major difference between the
distributions of the mRNAs encoding the two proteins was the presence
of only the
form of the enzyme in the white matter (in glial cells) and the choroid plexus. These results suggest that the functions of the
two enzymes cannot be distinguished based on tissue attributes, and
that very likely they subserve nonredundant functions probably within the same cell. This finding is consistent with the separation of
these two enzymes early in evolution (10, 33, 39).
The soluble type III PI 4-kinases have been described as targets of the
PI 3-kinase inhibitor, wortmannin, and it was found that their
inhibition leads to the rapid loss of receptor-regulated PtdIns(4)P and PtdIns(4,5)P2 pools in
several types of cells labeled with either
myo-[3H]inositol or
[32P]phosphate (27). Based on such evidence it
was postulated that one (or both) of these enzymes is responsible for
the maintenance of agonist-sensitive phosphoinositide pools (27).
Receptor-regulated generation of inositol lipid-based second messengers
is one of the most fundamental signaling mechanisms that regulates a
great variety of cellular responses. This process has been found to transmit signals from many classes of neurotransmitter receptors present in the brain, such as the muscarinic, -adrenergic,
serotoninergic, and metabotropic glutamate receptors. Lithium ions are
inhibitors at specific dephosphorylating steps of inositol-phosphate
metabolism and hence prevent efficient recycling of
myo-inositol in the brain, which relies on its own inositol
pool. It has been proposed that the therapeutic effect of
Li+ in the treatment of manic-depressive disease is related
to the ability of this ion to affect PI turnover (5).
Consistent with the importance of inositol lipid-based postreceptor
signaling in the brain, all major isoforms of PLC (,
, and
)
as well as the Ins(1,4,5)P3 receptor have been
found in the brain (32), and their mRNA distributions have been
determined (18, 26, 31, 36). However, recent advances in research on
neurotransmitter release indicate that inositides may also participate
in presynaptic events in addition to their above-discussed signaling
role (8). Among the proteins identified as critically important in
neurotransmitter release, both the GTPase protein, dynamin (34), and
the phosphoinositide phosphatase, synaptojanin (22), have been linked
to inositides. Dynamin has a pleckstrin homology domain, which is
believed to confer regulation by PtdIns(4,5)P2 to
the protein, whereas synaptojanin is a 5-phosphatase enzyme that, like
dynamin, associates with amphiphysin and undergoes dephosphorylation, presumably regulating the level of
PtdIns(4,5)P2 (reviewed in Ref. 8). Intriguingly, a
recent report identified Pik1, the yeast homologue of PI4K
, as a
binding partner for yeast Frq1, a yeast homologue of neuronal frequenin
(16). Frequenin, a member of the group of small
Ca2+-binding regulatory proteins, has been found to
modulate synaptic efficacy in neurons in Drosophila (29). These
recent findings confirm that inositol lipids possibly play a pivotal
role in neurotransmitter release and regulated secretion (21).
Expression of both forms of type III PI 4-kinases in the brain is
consistent with the importance of inositol lipid production and
metabolism in the regulation of these processes.
Given the prominent neuronal localization of both forms of type III PI
4-kinase, the presence of both mRNAs above the neuronal layers of the
retina is not surprising. However, their presence above the neurons of
the outer nuclear layer, where the cell bodies of the photoreceptors
are located, is of particular interest. Although the role of
phosphoinositide-based messengers in invertebrate photo-signal
transduction is firmly established, it is not clear if this system
plays any role in the vertebrate eye where the cGMP system is the
primary signaling mechanism (3). Six PLC isoforms have been isolated
from bovine retina yielding to the cloning of a then novel form,
PLC4, a putative functional homologue of the Drosophila
NorpA (20). The presence of PLC
4-like immunoreactivity in the
rod outer segment has also been demonstrated (28). These findings
suggest that inositide-based signaling may still be integrated into the
mammalian photosensory system, perhaps at the level of synapses.
Consistent with the ubiquitous role of inositide-based signaling, we
demonstrated the presence of the type III PI 4-kinase, especially the
smaller form, in peripheral tissues, although at a significantly
lower level than in the central nervous system. It is
noteworthy that a stronger signal was detected with the
-probe above
the kidney papilla corresponding to the cells of the collecting ducts,
and also over the duct of the salivary glands in the fetus. Moreover,
the choroid plexus and the ependymal lining of the ventricles also
showed a selective signal with the
-probe. This raises the
possibility that this enzyme may have an important role to play in
intracellular processes that participate in fluid transport. Although
there are reports on the role of PI 3-kinases (based on inhibitor
sensitivity) in transcytosis through epithelial cell layers (15), no
such data are available on PI 4-kinases.
Comparison of the results of our previous Northern blot analysis using
human mRNA (2; also see Ref. 23) and those of the current in situ
hybridization shows some discrepancies. In this regard it is important
to emphasize that the Northern analysis performed in the present study
with the same riboprobes used for the in situ studies and a commercial
mRNA blot (Clontech) showed very similar results to those described
earlier in the rat using mRNAs prepared by those investigators (24,
25). Strong signal was previously detected in the heart and skeletal
muscle with the -probe on Northern blot analysis of human tissues
(2, 23). However, this was not present in the rat, and both tissues showed very low expression of the two enzymes both by Northern analysis
and in situ hybridization. The reason for this discrepancy between human and rat tissues is not clear at present.
In summary, the present results demonstrate that type III PI 4-kinase
and
are ubiquitously expressed in various tissues, but show
predominant brain localization. Although these data are consistent with
the important signaling role of inositol lipids in neurotransmission,
they also suggest divergent, nonredundant functions of the two enzymes.
Future studies are aimed at defining these divergent roles to better
understand the complex regulatory role of inositol lipids in
controlling multiple cellular functions.
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ACKNOWLEDGEMENTS |
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We are most grateful to Dr. Eva Mezey (National Institute of Neurological Disorders and Stroke) for critical comments and guidance concerning the in situ hybridization technique and for the sections from rat embryos.
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FOOTNOTES |
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Present address of A. Zólyomi: Dept. of Radiology, Univ. Medical School of Pecs, H-7624, Pecs, Hungary.
The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. §1734 solely to indicate this fact.
Address for reprint requests and other correspondence: T. Balla, National Institutes of Health, Bldg. 49, Rm. 6A35, 49 Convent Dr., Bethesda, MD 20892-4510 (E-mail: tambal{at}box-t.nih.gov).
Received 9 August 1999; accepted in final form 1 December 1999.
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