Endocrinology Vol. 142, No. 7 3239-3243
Copyright © 2001 by The Endocrine Society
A Novel Function of Prolactin-Releasing Peptide in the Control of Growth Hormone via Secretion of Somatostatin from the Hypothalamus1
Norio Iijima2,
Yoshio Matsumoto2,
Takahiko Yano,
Masaki Tanaka,
Takanori Yamamoto,
Kenshi Kakihara,
Yuko Kataoka,
Yoshitaka Tamada,
Hirokazu Matsumoto,
Nobuhiro Suzuki,
Shuji Hinuma and
Yasuhiko Ibata
Departments of Anatomy and Neurobiology (N.I., M.T., Takan
Y., Y.I.), Anesthesiology (K.K.), Obstetrics and Gynecology (Y.K.),
Kyoto Prefectural University of Medicine, Kyoto 602-0841; Department of
Anatomy (Y.T.), Osaka Dental University, Osaka 573-1121; Discovery
Research Laboratories I (H.M., N.S., S.H.), Ibaraki 300-4293, Discovery
Research Laboratories III (Y.M., Takan Y.), Pharmaceutical
Discovery Research Division, Takeda Chemical Industries, Ltd.,
Osaka 532-8686, Japan
Address all correspondence and requests for reprints to: Yasuhiko Ibata, M.D., Ph.D., Department of Anatomy and Neurobiology, Kyoto Prefectural University of Medicine, Kawaramachi-Hiokoji, Kamikyo 602-0841, Japan. E-mail: yibata{at}basic.kpu-m.ac.jp
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Abstract
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The present study examined a novel function of PRL-releasing
peptide (PrRP) on the neuroendocrine. PrRP-immunoreactive nerve fibers
and nerve terminals were located in the vicinity of the somatostatin
(SOM)-neurons in the hypothalamic periventricular nucleus (PerVN).
Immuno-electron microscopy revealed that PrRP-immunoreactive nerve
terminals made synaptic contacts with nonimmunoreactive neuronal
elements in the PerVN. Intracerebroventricular (icv) administration of
PrRP induced immediate early gene, NGFI-A, in SOM-neurons in the
PerVN. Double-labeling in situ hybridization showed that
some parts of SOM-neurons in the PerVN expressed PrRP receptor
messenger RNA. Therefore, some parts of SOM-neurons in the PerVN
are considered to be directly innervated by PrRP via PrRP receptor. In
addition to the above morphological characteristics, icv administration
of PrRP decreased plasma GH levels. Such inhibitory effects of PrRP on
the secretion of GH from the anterior pituitary were diminished by
depletion or neutralization of SOM. From these findings it was strongly
suggested that SOM-neurons respond to PrRP and secrete SOM into the
portal vessels and thus inhibit GH secretion from the anterior
pituitary.
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Introduction
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PRL-RELEASING peptide (PrRP) was isolated
from bovine hypothalamus extract as a ligand of an orphan
seven-transmembrane receptor (hGR3), which was predominantly
expressed in the anterior pituitary. PrRP has two isoforms that consist
of 20 or 31 amino acids with a carboxyl-terminal amidation motif, which
are referred to as PrRP20 and PrRP31, respectively. Both PrRP showed
potent PRL releasing activity from cultured anterior pituitary cells
specifically (1). The iv administration of PrRP was shown
to induce increased plasma PRL levels (2, 3).
We previously reported the distribution of PrRP-immunoreactive
neurons, fibers, and nerve terminals by immunocytochemistry (4, 5). In that previous study, nerve-fibers with PrRP
immunoreactivity were widely distributed in the forebrain and
diencephalon. In the hypothalamus, many PrRP-fibers were predominantly
found within the paraventricular nucleus (PVN) and periventricular
nucleus (PerVN). On the other hand, Roland et al.
(6) reported that PrRP receptor messenger RNA (mRNA)
(rat’s counterpart of hGR3, UHR-1) was detected within the
PerVN and PVN. From these findings, we aimed to clarify whether PrRP
plays significant roles such as stimulation of some neuropeptide
synthesizing neurons in the PerVN and PVN other than the secretion of
PRL from the anterior pituitary. In the present study, we focused on
the effect of PrRP on somatostatin (SOM)-neurons in the hypothalamic
PerVN.
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Materials and Methods
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Animal
Male Wistar rats (8 weeks old) were purchased from
Charles River Laboratories, Inc. (Yokohama, Japan). They
were provided with food and water ad libitum, and kept under
the conditions of controlled lighting and temperature (22 C) until used
for experiments. All experiments in this study were carried out
following the NIH Guidance for the Care and Use of Laboratory Animals.
The Committee of Animals Research in Kyoto Prefectural University of
Medicine also approved the experiments.
Fluorescent double-labeling immunocytochemistry
Under deep pentobarbital anesthesia, animals were perfused
via the left cardiac ventricle with 150 ml 0.1 M phosphate
buffer containing 4% paraformaldehyde. Frozen frontal sections (25
µm thick) were made from the brain fixed with paraformaldehyde.
Fluorescent double-labeling immunocytochemistry was carried out using
monoclonal antibody P2L-1C against PrRP (50 µg/ml)
(7) and SOM (dilution 1:3000; Yanaihara Institute,
Shizuoka, Japan). As the second antibody, rhodamine-conjugated
antimouse IgG antibody for detection of PrRP and fluorescein
isothiocyanate-conjugated antirabbit IgG antibody for detection of
SOM were used, respectively. Preincubation of the antibody
P2L-1C with PrRP eliminated the immunoreactivity on the
sections.
Immuno-electron microscopy
Animals were perfused with 150 ml 0.1 M phosphate
buffer containing 5% acrorein. Serial frontal sections (30 µm thick)
were cut from tissue blocks of brains using a microslicer. The sections
were processed by the avidin-biotin complex (ABC) immunocytochemical
method using antibody against PrRP (P2L-1C) similar to the
initial immunoreactive staining of double-labeling immunocytochemistry
for ordinal light microscopy. After confirmation of the features of
PrRP-like immunoreactivity by light microscopy, the sections were
additionally fixed in chilled 1% OsO4 solution
for 1 h, dehydrated through a graded series of acetone, and
embedded in Epon 812 mixture. Ultrathin sections were stained with
uranyl acetate and lead acetate and examined with a JEM200CX electron
microscope (JEOL, Tokyo, Japan).
Intracerebroventricular (icv) administration of PrRP31 into
rats
Synthetic rat PrRP31 was prepared as described previously
(8). Rats were anesthetized by iv administration of
pentobarbital at 50 mg/kg, and then set in a rat brain stereotaxic
apparatus (Narishige, Tokyo, Japan). A stainless-steel guide cannula
(AG-12; EICOM, Kyoto, Japan) was inserted into the third ventricle (AP:
+7.1 mm from the interaural line, L: 0 mm from the midline, H: +2.0 mm
from the interaural line). These operated rats were housed in
individual cages and kept for at least 3 days for recuperation before
use in the experiments. Ten microliters of PBS with or without PrRP31
was injected into the third ventricle through a microinjection cannula
that was inserted into the guide cannula at a flow rate of 2.5
µl/min.
Neuronal response of hypothalamic SOM neurons after icv
administration of PrRP31
To clarify whether SOM-neurons were stimulated by PrRP, we
examined the immediate early gene product, NGFI-A (synonyms of
NGFI-A are Zif/268, ERG-1, or Krox24), after the icv administration of
PrRP31. This gene encodes a DNA-binding transcriptional factor with
zinc finger motifs and is used as a marker that is induced immediately
in a stimulated cell. For example, light-stimulation induced NGFI-A
expression in the SOM-neurons within the PerVN, which were stimulated
from the retinal ganglion cells via the neurons within the
suprachiasmatic nucleus (9). One hour after icv injection
of 10 nmol PrRP31 or PBS as described above, animals were perfused with
150 ml 0.1 M phosphate buffer containing 5% acrorein.
Frozen frontal sections (25 µm thick) were made. For double-labeling
immunocytochemistry for ordinal light microscopy,
NGFI-A-immunoreactivity was visualized by the ABC method using
anti-NGFI-antibody (dilution 1:2000; Santa Cruz Biotechnology, Inc., Santa Cruz, CA), with 3,3’-diaminobenzidine,
tetrahydrochloride (DAB) as chromogen. After this initial
immunoreactive staining, sections were treated with 0.3%
H2O2 for 30 min to
inactivate peroxidase in ABC, followed by incubation with anti-SOM
antibody (dilution 1:3000; Yanaihara Institute) for 3 days at 4 C.
After processing by the ABC method, chromogen benzidine dihydrochloride
was used to reveal SOM in the cytoplasm (10).
In situ hybridization
Animals were perfused via the left cardiac ventricle with 150 ml
0.1 M phosphate buffer containing 4% paraformaldehyde.
Frozen frontal sections (25 µm thick) of the brain were cut from each
animal, and then processed for in situ hybridization
according to the floating method as described previously (4, 9). The antisense RNA probe for rat PrRP receptor mRNA and the
rat SOM mRNA probe were synthesized from the coding region of rat
hGR3/UHR-1 complementary DNA (1116 bp) and SOM complementary DNA (400
bp) inserted into the plasmid vector pBluescriptII
(Stratagene, La Jolla, CA). Control sections
hybridized with each sense RNA probe did not show any positive signals
for PrRP mRNA. In the double-labeling study, both the
digoxigenin-labeled hGR3/UHR-1 RNA probe and
[35S]-CTP-labeled SOM RNA probe were
simultaneously used for the in situ hybridization.
After detection of hGR3/UHR-1 mRNA using alkaline-phosphatase with
4-nitroblue tetrazolium chloride and 5-bromo-4-chloro-3-indolyl
phosphate, the same sections were dipped in emulsion (Ilford K5)
and exposed for 4 days. After development, silver grains due to
[35S]-CTP-labeled SOM probe were detected in
the same neurons (9).
Assays of plasma GH after icv administration of PrRP31
The rats implanted with the guide cannula were anesthetized with
pentobarbital as described above, and then their bilateral jugular
veins were exposed. Before the icv injection of PrRP31, 600 µl blood
was withdrawn from the jugular vein and 20 U/ml heparin was immediately
added. Blood samples were subsequently prepared at 10, 20, 30, 40, and
60 min after the icv injection. By centrifugation, plasma was separated
from each blood sample, and then its GH concentration was determined
using a RIA system (Amersham Pharmacia Biotech, Little
Chalfont, UK).
Effects of GH-releasing hormone (GRH) on plasma GH after icv
injection of PrRP
After anesthetizing with pentobarbital, the rats implanted with
the guide cannula had the catheter inserted into the right jugular vein
1 day before icv injection of PrRP31. Before icv injection of PrRP31,
300 µl blood was withdrawn from the catheter of each rat and 20 U/ml
heparin was added immediately. Ten minutes after the PrRP31 injection,
GRH (Peptide Laboratories, Minoh, Japan) at the dose of 5
µg/kg dissolved in saline or saline alone was administrated to the
rat through the catheter. The administration of GRH was performed
between 1300 and 1600 h. Blood samples were subsequently prepared
at 10, 20, 30, 40, and 60 min after the GRH administration. The blood
was replaced each time with an equal volume of saline containing
heparin. GH concentrations in plasma samples were determined as
described above.
Effects of cysteamine and anticortistatin/SOM antibody on the
inhibition of GH secretion by PrRP31
Cysteamine hydrochloride was obtained from Wako Pure Chemical Industries, Ltd. (Osaka, Japan). Monoclonal
anticortistatin/SOM antibody (CIS-9) was raised against rat
cortistatin-14 conjugated with bovine thyroglobulin using
1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide as a coupling agent. The
splenocytes of mice immunized with the cortistatin-14-bovine
thyroglobulin conjugates were fused with mouse myeloma cells,
P3X63Ag8-U1, as described previously (11). Hybridoma cells
producing a monoclonal antibody, CIS-9 (IgG1, 
), were selected. The
antibody was purified from ascites fluid with a protein A-immobilized
column (IPA-300; Repligen, Cambridge, MA). In an enzyme immunoassay
using CIS-9, binding of biotin-labeled rat cortistatin-14 to CIS-9 was
inhibited by rat cortistatin-14, rat cortistatin-29, SOM-14, and SOM-28
with 50% inhibitory concentration values of 1.2, 0.9, 0.9, and
1.4 nM, respectively, indicating that CIS-9 fully
cross-reacted with SOM-14 and SOM-28.
Cysteamine (300 mg/kg, sc) and CIS-9 (1 mg/rat, iv) were administered
in rats 4 and 2 h before the GRH administration, respectively. The
administration of GRH and PrRP31, preparation of plasma samples, and
measurement of GH levels were performed in the same manner as described
above.
Statistical analyses
Values were expressed as the means ± SEM.
Differences between groups were analyzed by the two-tailed Student’s
t test. Aspin-Welch’s test was used when population
variances were not equal. Values of P < 0.05 were
considered statistically significant.
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Results
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Immunocytochemical analysis of PrRP-terminals within the
PerVN
PrRP-immunoreactive fibers and terminals were found
predominantly in the PerVN of the hypothalamus. A large number of
PrRP-immunoreactive nerve fibers were also detected around
SOM-immunoreactive neuronal elements using double-labeling
immunocytochemistry (Fig. 1A
).
Immuno-electron microscopy revealed that PrRP-immunoreactive axons made
synapses on nonimmunoreactive neuronal soma and dendrites (Fig. 1, B
and C).
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Figure 1. Double-labeling immunocytochemistry. A, The
arrows show the P2L-1C-immunoreactive fibers
(fluorescein isothiocyanate-labeled) in the vicinity of SOM-neuronal
perikarya (rhodamine-labeled) within the PerVN in the hypothalamus.
Immuno-electron microscopy using P2L-1C in the PerVN in the
hypothalamus. PrRP-immunoreactive nerve fibers show the intimate
contact with nonimmunoreactive neuronal somata (B) or to make the
synapse in nonimmunoreactive dendrites (C). The arrow
indicates the synaptic contact. A, Bars, 10 µm; B and
C, bars, 1 µm.
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Neuronal response to icv administration of PrRP and its receptor
within the PerVN
To clarify the SOM neuronal response to PrRP, expression of NGFI-A
was examined by immunocytochemistry using antibodies against NGFI-A and
SOM. After icv administration of PrRP31, NGFI-A was detected in the
nuclei of many neurons within the PerVN especially in the SOM neurons;
92% of SOM neurons revealed NGFI-A immunoreactivity (Fig. 2A). However, NGFI-A was never detected
in the neurons of the hypothalamic PerVN of PBS-injected animals (Fig. 2B).
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Figure 2. Double-labeling immunocytochemistry for NGFI-A and
SOM in the PerVN. A, Several SOM-neurons expressed NGFI-A protein in
their nucleus after icv administration of PrRP. B, No signal of NGFI-A
was detected in the nucleus of SOM-neurons in the rat brain injected
with PBS. Bars, 10 µm.
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Double-labeling in situ hybridization, which detected both
PrRP receptor mRNA and SOM mRNA simultaneously showed that PrRP
receptor mRNA was located in 32% of neurons with SOM mRNA signals in
the hypothalamic PerVN (Fig. 3).
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Figure 3. Double-labeling in situ
hybridization of PrRP receptor mRNA (DIG-stained cell) and SOM mRNA
(accumulation of silver grains). Arrows indicate neurons
coexpressing purple colored PrRP receptor mRNA and SOM mRNA as silver
grains. Bars, 10 µm.
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The effect of icv administration of PrRP31 on plasma GH
levels
To determine whether PrRP can directly act on SOM-neurons, we
administrated PrRP31 into the third ventricle and then examined the
change in plasma GH levels. As shown in Fig. 4 at 10 min after icv administration of
PrRP, GH in the plasma was significantly decreased and this level was
maintained for 40 min in which we examined GH at 20, 30, and 40 min
after icv administration of PrRP compared with that in the animals
administered PBS.
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Figure 4. Effects of icv administeration of PrRP31 on plasma
GH levels in rats. After icv administration of PrRP31 at 50 nmol (•)
or PBS alone ( ), plasma samples were prepared from rats at the
intervals indicated in the figure. The numbers of rats used for PrRP
and PBS administration were 8 and 7, respectively. Each value of the GH
concentration represents the mean ± SEM. *,
P < 0.05; **, P < 0.01,
comparing the PrRP31-injected group with the PBS-injected group.
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The effect of icv administration of PrRP31 on the plasma GH
secretion induced by GRH
We measured plasma GH after iv injection of GRH. Plasma GH
samples were examined at 10, 20, 30, 40, and 60 min after GRH injection
and the peak was at 10 min (Fig. 5). In
addition, we examined how PrRP influenced GH secretion induced by GRH.
As a control of GRH injection on the plasma GH level, the plasma GH
level was 37.5 ± 15.8 ng/ml after icv injection of PBS followed
by iv injection of saline (PBS plus saline); however, the plasma GH
level was increased to 536.4 ± 106.4 ng/ml after icv injection of
PBS followed by iv injection of GRH (PBS plus GRH). The plasma GH
levels elevated by GRH were inhibited by icv injection of PrRP in a
dose-dependent manner. Plasma GH became 262.4 ± 38.3 ng/ml at 10
min after 1 nmol PrRP injection (PrRP plus GRH), compared with (PBS
plus GRH) and become 67.0 ± 26.1 ng/ml at 10 min after a 50-nmol
injection of PrRP (PrRP plus GRH), compared with that of PBS plus
GRH.
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Figure 5. The effect of PrRP31 on the plasma GH levels
elevated by GRH in rats. After icv injection of PrRP, 5 µg/kg GRH was
iv injected into rats, and then plasma samples were prepared at the
intervals indicated in the figure. , PBS plus saline, icv injection
of PBS followed by iv injection of saline; •, PBS plus GRH, icv
injection of PBS followed by iv injection of GRH;  , 0.1 nmol PrRP
plus GRH, icv injection of 0.1 nmol PrRP31 followed by iv injection of
GRH;  , 1 nmol PrRP plus GRH, icv injection of 1 nmol PrRP31 followed
by iv injection of GRH; x, 50 nmol PrRP plus GRH, icv injection of 50
nmol PrRP31 followed by iv injection of GRH. The numbers of rats used
for these experiments were 7, 9, 11, 8, and 8, respectively. Each GH
concentration value represents the mean ± SEM.
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Effect of pretreatment of cysteamine on GH secretion by
PrRP31
We examined the effect of a SOM-depletor, cysteamine (12, 13, 14). As shown in Fig. 6, icv
administration of PrRP31 at 5 nmol significantly reduced the elevated
plasma GH levels at 10 min after the iv GRH administration; that is,
the plasma GH levels of PBS+GRH were 536.4 ± 106.4 ng/ml, whereas
those of PrRP+GRH were 220.8 ± 64.4 ng/ml (P <
0.05). However, pretreatment with 300 mg/kg cysteamine induced
increases in plasma GH levels and evidently abolished the inhibitory
effect of PrRP31, i.e. the plasma GH levels of Cys plus PBS
plus GRH were 639.0 ± 76.0 ng/ml, whereas those of Cys plus PrRP
plus GRH were 569.1 ± 62.2 ng/ml.
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Figure 6. The effect of cysteamine and anticortistatin/SOM
antibody on the inhibition of GH secretion by PrRP31 in rats. Rats
pretreated with 300 mg/kg cysteamine or a monoclonal
anticortistatin/SOM antibody (CIS9, 1 mg/rat), or nontreated rats were
subjected to icv injection of PrRP (5 nmol) followed by iv injection of
GRH (5 µg/kg), and then their plasma samples were prepared 10 min
after the GRH injection. PBS, icv injection of PBS alone followed by iv
injection of GRH under the condition without cysteamine treatment;
PrRP, icv injection of PrRP31 followed by iv injection of GRH under the
condition without cysteamine treatment; Cys+PBS, icv injection of PBS
alone followed by iv injection of GRH after cysteamine treatment;
Cys+PrRP, icv injection of PrRP31 followed by iv injection of GRH after
cysteamine treatment. CIS9 plus PBS, icv injection of PBS alone
followed by iv injection of GRH after antibody treatment; CIS9 plus
PrRP, icv injection of PrRP31 followed by GRH after antibody treatment.
The numbers of rats used for these experiments were 9, 10, 7, 8, 7 and
8, respectively. Each GH concentration value represents the mean
± SEM. *,P < 0.05, when comparing
the PrRP group with the PBS group.
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To confirm that SOM was involved in the inhibitory effect of
PrRP31 on the GH secretion, we examined the effect of a monoclonal
antibody that is capable of neutralizing the activity of SOM. As shown
in Fig. 6
, pretreatment with the antibody (150 mg/kg) induced a marked
increase in the plasma GH level and evidently abolished the inhibitory
effect of PrRP31, i.e. the plasma GH levels of antibody
(CIS9) plus PBS plus GRH were 1239.8 ± 129.8 ng/ml,
whereas those of CIS9 plus PrRP plus GRH were 1041.2 ± 52.1
ng/ml. Considering these findings together with the observations using
cysteamine, PrRP31 was suggested to have inhibitory effects on GH
secretion through the promotion of SOM (and cortistatin) secretion in
the hypothalamus.
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Discussion
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Immunocytochemical analysis of PrRP with respect to the
morphological interaction of SOM-neurons in the PerVN
In the present study, we revealed the morphological correlation
between PrRP and the SOM-neurons within the PerVN. In the hypothalamus,
the most prominent innervation of PrRP-immunoreactive fibers was found
in the PerVN. Double-labeling immunocytochemistry using antibodies
against SOM and PrRP clearly revealed that PrRP-immunoreactive fibers
surrounding the SOM-immunoreactive neuronal perikarya and processes by
confocal microscopy. Moreover, immuno-electron microscopy using
antibody against PrRP showed the nerve terminals with
PrRP-immunoreactivity formed the synaptic contacts with
nonimmunoreactive neuronal elements within the PerVN, a significant
number of which may belong to the SOM-neurons. Therefore, within the
PerVN, PrRP may play a role as a neuromodulator or a neurotransmitter.
The icv administration of PrRP induced the expression of NGFI-A in the
majority of SOM-neurons within the PerVN. These findings strongly
suggested that such SOM-neurons within the PerVN could be stimulated by
PrRP injected into the ventricle. Moreover, some SOM-neurons expressed
PrRP receptor mRNA. These neurons might be directly innervated by
PrRP-nerve fibers.
Physiological analysis of PrRP to inhibit GH release
through direct stimulation of SOM neurons
Secondly, we showed physiological evidence that PrRP could
regulate plasma GH levels by direct stimulation of SOM. The icv
administration of PrRP induced a rapid decrease in plasma GH levels.
High dose injection of PrRP almost completely inhibited the increase in
plasma GH levels induced by iv injection of GRH. After cysteamine
pretreatment, which depleted SOM or anticortistatin/SOM antibody, PrRP
never depressed the plasma GH levels. These findings suggested that
PrRP inhibited the plasma GH level via stimulation of SOM production or
secretion into the portal vessel through the median eminence. As
summarized by the immunocytochemical and physiological evidence,
the following was suggested; PrRP could stimulate SOM-neurons
within the PerVN, as a neuromodulator or neurotransmitter via synaptic
contacts, to secrete SOM into the portal vessels and finally inhibit GH
secretion from the anterior pituitary.
Additional suggestions for the function of PrRP
Hinuma et al. (1) discovered
PrRP and reported that PrRP has an ability to release PRL from the
anterior pituitary cells. Recently, PrRP was additionally reported to
affect several hypothalamic hormones. For example PrRP stimulated
oxytocin neurons and CRH neurons in the hypothalamus by directly
innervation (15, 16). The icv administration of PrRP
increased the plasma level of oxytocin and the plasma level of ACTH due
to stimulation of CRH. However, it was not clarified whether SOM-,
CRH-, or oxytocin-neurons were stimulated by PrRP simultaneously or
respectively in the different situations in intact rat brains. In
addition, PrRP was reported to contribute to the endocrine or autonomic
nervous systems (17, 18, 19). The variety of the functional
roles of PrRP remains to be fully elucidated.
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Footnotes
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1 This work was supported in part by a grant (11480240) from the
Ministry of Education, Science, Sports, and Culture, Japan. 
2 These authors contributed equally to this work.
Received November 16, 2000.
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Abstract
Introduction
