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1 Department of Physiology, Miyazaki Medical College, 5200 Kihara, Kiyotake, Miyazaki 889-1692, Japan; 2 Department of Anesthesiology, Miyazaki Medical College, 5200 Kihara, Kiyotake, Miyazaki 889-1692, Japan; 3 Department of Internal Medicine, Miyazaki Medical College, 5200 Kihara, Kiyotake, Miyazaki 889-1692, Japan; 4 Department of Public Health, Miyazaki Medical College, 5200 Kihara, Kiyotake, Miyazaki 889-1692, Japan
Submitted 10 March 2003; accepted in final form 11 April 2003
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONMETHODSRESULTSDISCUSSIONDISCLOSURESREFERENCES |
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONMETHODSRESULTSDISCUSSIONDISCLOSURESREFERENCES |
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;
Minamino et al. 1985) and has
potent effects on smooth muscle. The two receptors for NMU, NMU-R1 and NMU-R2,
are G protein-coupled receptors (GPCRs)
(Howard et al. 2000). NMU-R2 is
expressed in the paraventricular nucleus (PVN) of the rat hypothalamus
(Raddatz et al. 2000). NMU
induces extracellular acidification, arachidonic acid metabolite release, and
intracellular Ca2+ mobilization in cells expressing
NMU-R1 or NMU-R2 (Howard et al.
2000; Shan et al.
2000). Recently, we found that intracerebroventricular (icv)
administration of NMU can provoke an increase in mean arterial blood pressure
(MABP), heart rate (HR), and plasma norepinephrine. This suggests that NMU
regulates sympathetic nervous system activity and affects cardiovascular
function (Chu et al. 2002).
Conductance of K+ and Na+ by IH
channels is activated by membrane hyperpolarization, gated by cyclic
nucleotides (cAMP, cGMP), and is blocked by extracellular Cs+ and
ZD 7288, a selective blocker of IH
(Ghamari-Langroudi and Bourque
2000; Harris and Constanti
1995; Ludwig et al.
1998; Moosmang et al.
2001; Santoro et al.
1998). IH mediates inward rectification of the
membrane in response to voltage changes. It has also been functionally
implicated in maintaining resting membrane potential (RMP), thereby providing
an excitatory drive that contributes to phasic and tonic firing
(Doan and Kunze 1999;
Ghamari-Langroudi and Bourque
2000). Four different isoforms of the IH
channel have been cloned, and two different isoforms (HCN1 and HCN3) are
highly expressed in rat PVN (Monteggia et
al. 2000).
Because IH channels and NMU receptors are both present in rat PVN, the goal of the present study was to determine the effect of NMU activation on IH channels and PVN neuron activity. We used a whole cell patch-clamp method to examine the effects of NMU on rat PVN neurons in vitro.
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METHODS |
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TOPABSTRACTINTRODUCTIONMETHODSRESULTSDISCUSSIONDISCLOSURESREFERENCES |
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Hypothalamic slices were prepared from P12- to P14-day-old male Wistar
rats, as previously described (Shirasaka
et al. 2001). All experiments were approved by the Ethics
Committee of the Miyazaki Medical College and were in accordance with
international guidelines on the ethical use of animals in laboratory
experiments. Briefly, the brain was quickly removed and placed into ice-cold
artificial cerebrospinal fluid (ACSF) consisting of (in mM) 140 NaCl, 3 KCl,
1.3 MgSO4, 1.4 NaH2PO4, 11
D-glucose, 5 HEPES, 2.4 CaCl2, and 3.25 NaOH. The pH was
7.3; the osmolarity was 290–300 mOsm, and the fluid was bubbled with
100% O2. Coronal slices were 250 µm in thickness, including PVN,
and were prepared using a vibrating brain slicer (DSK-2000; Dosaka, Kyoto,
Japan). The slices were incubated for 
1 h in a chamber filled with
equilibrated ACSF at room temperature (24–26°C) before recordings
were started.
Electrophysiology
Patch pipettes were made with a puller (PB-7; Narishige, Tokyo) from
thick-wall borosilicate glass (GD-1.5; Narishige). They were filled with a
solution consisting of (in mM) 130 potassium gluconate, 10 HEPES, 10 KCl, 1
CaCl2, 5 EGTA, 1 MgCl2, 2 Na2ATP, and 0.5
Na3GTP. The pH was adjusted to 7.2 with KOH. Patch pipette
resistances were 5–7 M
in the bath, with series resistances in
the range of 10–20 M, compensated by 80%. The liquid junction
potential (10 mV) was corrected for according to the method described by Neher
(1992). Membrane potentials
and/or currents were monitored with an Axopatch 200B amplifier (Axon
Instruments, Foster City, CA), acquired through a Digidata 1200 series A/D
interface on a personal computer using Clampex 7.0 software (Axon
Instruments). Selected traces were saved to the hard drive of a computer, and
all data were saved to a 4.7-GB DVD-RAM.
The membrane potential and current were low-pass-filtered at 1–5 KHz.
Whole cell recordings were made from microscopically identified cells. Once
stable recording conditions were obtained, a PVN neuron was identified
electrophysiologically as type I (magnocellular) or type II (parvocellular)
according to previously established criteria by current-clamp in standard ACSF
(Luther et al. 2000). Type I
neurons displayed transient outward rectification, while Type II did not. In
voltage-clamp, TTX was routinely included in external recording solutions to
block voltage-gated Na+ channels.
Chemicals
Reagents included rat NMU-23 (Peptide Institute, Japan), ZD 7288 (Tocris Cookson, Ballwin, MO), CsCl (Sigma, St. Louis, MO), and TTX (Sigma). ZD 7288 was prepared as a 50 mM stock solution (in H2O) and stored at –20°C until use. The other drugs were dissolved in ACSF.
Data analysis
Data were analyzed using Clampfit 8.0 (Axon Instruments) and are expressed
as mean ± SE. IH was determined by subtracting
IIns from Iss at each hyperpolarizing
voltage step using the equation
 | (1) |
) as follows
 | (2) |
Differences between mean values recorded under control and test conditions were evaluated using Student's t-test or one-way ANOVA with Tukey's post-hoc test. Differences were considered significant at P < 0.05.
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RESULTS |
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TOPABSTRACTINTRODUCTIONMETHODSRESULTSDISCUSSIONDISCLOSURESREFERENCES |
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A total of 309 PVN neurons (66 type I, 243 type II) were sampled under
whole cell current-clamp conditions. While none of the type I neurons showed a
response to NMU, 76 of the type II neurons (31%) were sensitive to NMU. These
neurons expressed a depolarizing response approximately 1 min after
application of 100 nM NMU; specifically, they displayed time-dependent inward
rectification during the hyperpolarizing pulses
(Fig. 1, C and
D) that was blocked by 70 µM ZD 7288
(Fig. 1B) or 3 mM
Cs+ (not shown). These characteristics are consistent with
IH conductance (Ludwig
et al. 1998; Santoro et al.
1998). Further, the responsive neurons exhibited a lack of
transient outward rectification in response to a series of depolarizing
current pulses delivered at a hyperpolarized membrane potential
(Fig. 1A)
(Luther et al. 2000).
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Effects of NMU on membrane potential
Applications of NMU in concentrations ranging from 10 nM to 1 µM NMU resulted in depolarization and increased firing rate in a concentration-dependent manner in MNU-sensitive PVN neurons when the holding potentials were –60 mV (Fig. 2); however, the characteristics of the action potentials were not changed (not shown). The depolarization response appeared approximately 40 s after NMU exposure and peaked at approximately 100 s, with a maximal depolarization range of 1.75 ± 0.47 to 7.18 ± 1.21 mV (Fig. 2C). The minimum NMU dose required to elicit an effect on membrane potential was 1 nM, and the maximum dose was approximately 1 µM. The EC50 was approximately 70 nM. This response was unaffected by the presence of 0.5 µM TTX + 10 µM 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX) + 10 µM bicuculline (7.18 ± 1.21 mV in the presence of 1 µM NMU, 6.79 ± 1.13 mV in the presence of TTX, CNQX, and bicuculline following the application of 1 µM NMU; mean ± SE, P > 0.05, n = 5).
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Effects of NMU on membrane current
Application of 1 µM NMU to NMU-sensitive neurons with voltage-clamp at
–60 mV produced a negligible inward current (7.5 ± 2.1 pA,
n = 16). However, when neurons were held at –60 mV and a series
of 1-s hyperpolarizing voltage steps were held from –60 to –150
mV, NMU induced a significant increment in steady-state current
(Iss) at step potentials less than –80 mV
(Fig. 3, A and
B, P < 0.05, n = 7) and
instantaneous current (IIns) at step potentials less than
–100 mV (Fig. 3, A and
C, P < 0.05, n = 7). NMU-induced
increases in IIns was not affected by
Ba2+ (Fig.
4A), but was blocked by ZD 7288
(Fig. 5C) or
Cs+ (not shown). Simultaneously, the net reversal potential of the
NMU-sensitive component of the fast current (determined in the presence of 100
µM Ba2+) was compared with the reversal potential for
IH (also determined in the presence of 100 µM
Ba2+) (Cardenas et
al. 1999). As illustrated in
Fig. 4, A and
B, the reversal potential was –34.0 ± 2.6 mV
(n = 4) under control and NMU conditions. This was similar to the
reversal potential of –33.5 ± 2.1 mV (n = 4) obtained
with another group of NMU-sensitive neurons for the portion of
IIns which was increased by changing the holding potential
from –60 to –80 mV in the presence of Ba2+
(Fig. 4, C and
D). Thus the increase in IIns
produced by the shift in holding potential likely reflects an increase in
tonically open IH channels
(Mayer and Westbrook
1983).
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Blockade of the effects of NMU by ZD 7288 or Cs+
In current clamp, NMU-induced depolarization was not affected by TTX
(Fig. 5A). However,
application of ZD 7288 induced slight hyperpolarization in NMU-sensitive PVN
neurons and abolished NMU-induced depolarization
(Fig. 5B). NMU
increased Iss and IIns according to
hyperpolarizing pulses. To determine whether NMU-induced increase in
ISS and IIins represented enhanced
IH channels, ZD 7288 and Cs+ (not shown) were
used as IH channel blockers
(Harris and Constanti 1995;
Maccaferri and McBain 1996;
McCormick and Pape 1990;
Pape 1996). ZD 7288
significantly blocked IIns and NMU-induced increments of
IIns at step potentials less than –80 mV. The
I-V relationships were linear in the presence of ZD 7288
(Fig. 5, C and
D). Further, ZD 7288 blocked Iss and
NMU-induced increments of Iss at step potentials less than
–80 mV. The I-V relationships were also linear in the presence
of ZD 7288 (Fig. 5, C and
E). This finding indicates that NMU-sensitive neurons
have IH channels, which produce
hyperpolarization-activated ZD 7288-sensitive inward currents
(IH) and are activated at RMP, thus producing ZD 7288
sensitive IIns.
Effects of NMU on IH
In this study, 1 µM NMU significantly enhanced IH
activity at step potentials less than –80 mV, and the maximal effects
were at step potentials of –100 to –120 mV
(Fig. 3D).
Furthermore, we estimated the effect of NMU on IH
conductance (GH) (see METHODS),
EH, was obtained in the NMU-sensitive neurons as shown in
Fig. 6A: following a
step to –120 mV (1-s duration), the membrane voltage was stepped in the
range of –110 to –50 mV (1-s duration, 10-mV increments)
(Maccaferri and McBain 1996).
The plot of the instantaneous current at each test potential yielded the fully
activated I-V relationship, which was linear
(Fig. 6B). The
extrapolated reversal potential (EH) was –33.1
± 1.8 mV (Fig.
6B, n = 5), similar to that previously reported
for EH in other nervous preparations
(Maccaferri and McBain 1996;
McCormick and Pape 1990;
Pape 1996). The mean
GH-V relations are shown in
Fig. 6C. Note that NMU
enhanced IH conductance at step potentials more negative
than –80 mV (P < 0.05, n = 7). Furthermore, the
modified Boltzmann equation was used as follows
 | (3) |
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Effects of NMU on the kinetics of IH activation
The time course of activation of IH was obtained from
an analysis of the rising phase of the NMU-induced IH
current evoked by hyperpolarizing steps to various voltages. As shown in
Fig.
6D1, the IH
current traces were fit to a single exponential function of the form
At = A
(1 –
e–t/
),
where At is the amplitude of
IH at time t, A is the amplitude of
IH at a steady state, and is the activation time
constant (Ghamari-Langroudi and Bourque
2000). Figure
6D2 reveals the plots of the means
± SE (n = 7) against voltage steps. The of NMU-sensitive
neurons decreased from 800 ms at –70 mV to 100 ms at –140 mV and
exhibited fast kinetics. NMU enhanced IH channels kinetics
exhibiting decrements of at step potentials more negative than
approximately –80 mV (P < 0.05 vs. ACSF, n =
7).
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DISCUSSION |
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TOPABSTRACTINTRODUCTIONMETHODSRESULTSDISCUSSIONDISCLOSURESREFERENCES |
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Expression of IH in PVN NMU-sensitive neurons
In the present study, NMU-sensitive PVN neurons displayed a time-dependent
strong inward rectification during hyperpolarizing pulses
(Fig. 1, C and
D) that was blocked by 70 µM ZD 7288
(Fig. 1B). Further,
these neurons did not display transient outward rectification. These
properties are consistent with IH conductance produced by
IH channels (Ludwig et
al. 1998; Luther et al.
2000; Santoro et al.
1998; Stern 2001;
Tasker and Dudek 1991).
NMU excited PVN NMU-sensitive neurons by enhanced IH
NMU evoked small depolarization and increased neuronal excitability.
Several previous studies have demonstrated that enhancement of
IH results in increased neuronal excitability and
responsiveness to excitatory input. This occurs via release of neurons from
tonic hyperpolarizing synaptic input and via facilitation of action potential
triggering by depolarizing input or counter-balancing after-hyperpolarizations
following action potentials (Pape
1996; Pape and McCormick
1989; Yagi and Sumino
1998). The presence of IH in magnocellular
neurosecretory cells of rat supraoptic nucleus provides an excitatory drive
that contributes to phasic and tonic firing
(Ghamari-Langroudi and Bourque
2000). IH plays a significant role in setting
both the RMP and the baseline level of excitability of hippocampal GABAergic
interneurons found in the stratum oriens of area CA1
(Lupica et al. 2001).
Several findings in the current study suggest that NMU excites PVN neurons
via enhanced IH channel activity. First, the RMP of
NMU-sensitive neurons was approximately –58 mV (Vh =
–60 mV), and the EH was approximately –33 mV
(Fig. 6B), suggesting
that IH channels are partially active at RMP
(Yagi and Sumino 1998). NMU
enhanced the activity of IH channels at RMP, induced
NMU-sensitive neurons depolarizing in current-clamp
(Fig. 2), and evoked increments
of IIns by hyperpolarizing steps
(Fig. 3C). NMU-induced
increment in IIns was almost completely blocked by ZD 7288
(Fig. 5C), but not by
Ba2+ (Fig. 4,
A and B). Thus this likely reflects an increase
in tonically activated IH
(Mayer and Westbrook 1983).
Second, in voltage clamp, NMU resulted in an increase of
IH current and enhanced channel kinetics at step
potentials less than –80 mV. NMU also produced a significant shift in
V1/2 to a more depolarized potential. Third, ZD 7288
completely blocked NMU-induced depolarization
(Fig. 5B) and
abolished the effects of NMU on the neurons in voltage clamp
(Fig. 5, C, D, and
E). Collectively, these data suggest that NMU enhanced
IH, resulting in a shift in the membrane potential toward
more depolarized levels and firing action potential.
In this study, NMU resulted in depolarization of membrane potential in a
dose-dependent manner with an EC50 of 70 nM. However, NMU did not
induce large depolarization, likely because IH maintains
the membrane potential of neurons within the range necessary for the
generation of tonic action potential firing
(Ghamari-Langroudi and Bourque
2000; Williams et al.
2002). Recently, it was reported that icv administration of NMU
induced c-fos expression in magnocellular cells (type I) and
parvocellular cells (type II) (Ozaki et
al. 2002). The expression of the c-fos gene in the PVN
should reflect the neural activation either directly or indirectly after icv
administration of NMU (Ozaki et al.
2002). NMU-R2 is expressed in the PVN of the hypothalamus, along
the wall of the third ventricle in the hypothalamus
(Howard et al. 2000). In this
study, NMU-induced responses in membrane potential were unaffected by TTX +
CNQX + bicuculline. This evidence suggests that NMU depolarizes PVN type II
neurons via a direct postsynaptic action rather than by indirect modulation of
neurotransmission. On the other hand, none of the type I neurons showed a
response to NMU. According to our data, we suggest that the expression of the
c-fos gene in the PVN magnocellular may be mainly via an unknown
indirect pathway after icv administration of NMU.
Possible mechanism of NMU action
NMU-R2 is expressed in the PVN of the rat hypothalamus
(Howard et al. 2000), and HCN1
and HCN3 mRNA expression is highly enriched in the PVN
(Monteggia et al. 2000). It is
possible that PVN NMU-sensitive PVN neurons contain IH
(HCNs) channels and NMU-R2. A key property of neuronal HCN channels is their
regulation by neurotransmitters and hormones that act via cAMP, cGMP, or
intracellular Ca2+
(Pape 1996). The cAMP and cGMP
affect HCN channels by directly interacting with the cyclic nucleotide-binding
domain protein of the C-terminus (Ludwig
et al. 1998). The increment of intracellular
Ca2+ in thalamic relay cells can result in modifications
of IH that are similar to those observed following
increases in cAMP (Lüthi and
McCormick 1998). NMU-R1 is coupled to phospholipase C stimulation
via a Gq-type G protein, resulting in the release of the
inositol phosphate (IP) second messenger and increased intracellular
Ca2+ in COS-7 cells
(Raddatz et al. 2000). NMU-R2
is also coupled to the Gq family of G proteins in cells,
inducing a rapid increase in intracellular Ca2+
(Shan et al. 2000). In
thalamic neurons, transient increases in intracellular
Ca2+ appeared to cause a reversible augmentation of
IH attributable to the rapid,
Ca2+-dependent formation of cyclic nucleotides
(Lüthi and McCormick
1998). The increment of intracellular Ca2+
activates soluble guanylate cyclase, leading to increased cGMP levels
(Kuzmiski and Macvicar
2001).
Thus we propose that NMU binds to NMU-R2, resulting in increased intracellular calcium and cGMP. This leads to an increment in IH current and neuronal excitation. This response may contribute to activation of autonomic centers in the brain stem and spinal cord that regulate MABP, HR, and plasma norepinephrine.
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DISCLOSURES |
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TOPABSTRACTINTRODUCTIONMETHODSRESULTSDISCUSSIONDISCLOSURESREFERENCES |
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FOOTNOTES |
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Address for reprint requests: H. Kannan, Department of Physiology, Miyazaki Medical College, 5200 Kihara, Kiyotake-cho, Miyazaki-gun, Miyazaki 889-1692, Japan (E-mail: kannanh{at}post.miyazaki-med.ac.jp).
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) and at the
steady-state voltage (
) during the hyperpolarizing pulses.
) against the membrane potential (
),
during the application of NMU (
) against the membrane potential. Note
that NMU increased IH at step potentials less than
–80 mV. All data are mean ± SE; n = 7, *P <
0.05 vs. ACSF.
). Note that 70 µM ZD 7288
abolished the effects of NMU. All data are mean ± SE, n =
6.