| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
|
|
|
|||||||
|
|||||||||
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Department of Anaesthesiology, The Pennsylvania State University College of Medicine, The Milton S. Hershey Medical Center, Hershey, PA 17033, USA
 |
Abstract |
|---|
 Top Abstract IntroductionMethodsResultsDiscussionReferences |
|---|
(Received 14 August 2003;
accepted after revision 10 October 2003;
first published online 10 October 2003)
Corresponding author H.-L. Pan: Department of Anaesthesiology, The Pennsylvania State University College of Medicine, The Milton S. Hershey Medical Center, Hershey, PA 17033, USA. Email: hpan{at}psu.edu
|
Introduction |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
As a membrane-permeant neuronal messenger in the central nervous system, NO produces its biological actions through distinct signal transduction pathways (Stamler et al. 1997; Ahern et al. 2002). Besides the modification of proteins involved in its action through S-nitrosylation (Jaffrey et al. 2001) or formation of peroxynitrite (Stamler et al. 1992; Trabace & Kendrick, 2000), NO initiates a signalling cascade by activating the soluble isoform of guanylyl cyclase (sGC) and subsequently elevates intracellular concentration of 3',5'-cyclic guanosine monophosphate (cGMP) (Matsuoka et al. 1992; Southam & Garthwaite, 1993; Wood & Garthwaite, 1994). The principal targets of cGMP are cGMP-gated channels (Zagotta & Siegelbaum, 1996), cGMP-dependent phosphodiesterases (Pineda et al. 1996; Kraus & Prast, 2002), and cGMP-stimulated protein kinase G (PKG) (Jaffrey & Snyder, 1995). The NO–cGMP–PKG signalling pathway may be important in regulation of neuronal excitability and neurotransmission at pre- and postsynaptic sites. In this regard, L-arginine and sodium nitroprusside can increase neuronal excitability and dye coupling of supraoptic nucleus neurones through cGMP-dependent mechanisms in rats (Yang & Hatton, 1999). Also, a NO donor, S-nitroso-N-acetyl-penicillamine (SNAP), and a cGMP analogue, 8-Br-cGMP, increase the firing activity of neurones in the locus coeruleus (Pineda et al. 1996). In vivo microdialysis studies have shown that SNAP or 8-Br-cGMP increases the release of acetylcholine, glutamate, and GABA in the striatum (Guevara-Guzman et al. 1994; Trabace & Kendrick, 2000). Furthermore, the cGMP analogue pCPT-cGMP facilitates glutamate release in the nerve terminals (Klyachko et al. 2001). The PVN is not only rich in neuronal NO synthase (nNOS) but also in both the 
1 and ß1 subunits of sGC (Furuyama et al. 1993; Li et al. 2002). However, the functional role of cGMP and sGC in NO-induced synaptic GABA release in the PVN has not been determined previously.
Neurotransmitter release from the nerve terminals is generally thought to be mediated by a Ca2+-dependent mechanism. However, the effect of NO on the synaptic neurotransmitter release appears to be an exception. In this regard, NO can stimulate Ca2+-independent glutamate release from hippocampal synaptosomes (Meffert et al. 1994). Also, 8-Br-cGMP has little effect on both resting potential- and action potential-dependent increments of Ca2+ concentration in presynaptic terminal although it can potentate neurotransmitter release (Yawo, 1999). It has been suggested that NO-stimulated vesicle release is probably mediated through modulating synaptic vesicle docking and fusion reactions (Meffert et al. 1996). In the CNS, the effect of NO on neurotransmitter release is site specific with regard to the type of neurone and neurotransmitter. It has been shown that the effect of NO appears to be cell-type specific in the hypothalamus (Yang & Hatton, 1999; Ozaki et al. 2000; Li et al. 2002). In the present study, we used a combination of retrograde tracing and in vitro whole-cell recordings to determine the signal transduction mechanisms involved in NO-induced presynaptic GABA release to spinally projecting PVN neurones.
|
Methods |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
Sprague-Dawley rats (4–6 weeks old; Harlan, Indianapolis, IN, USA) of either sex were used for this study. The surgical preparations and experimental protocols were approved by the Animal Care and Use Committee of the Pennsylvania State University College of Medicine and conformed to the NIH guidelines on the ethical use of animals. All efforts were made to minimize both the suffering and number of animals used. The rat spinal cord at the T1–T4 level was exposed through dorsal laminectomy under halothane anaesthesia. A rhodamine-labelled fluorescent microsphere suspension (FluoSpheres, 0.04 µm, Molecular Probes, Eugene, OR, USA) was pressure-ejected (Picospritzer II, General Valve Co., Fairfield, NJ, USA) bilaterally into the region of the intermediolateral cell column of the spinal cord in 2 or 3 separate 50 nl injections using a glass micropipette (20–30 µm tip diameter). The pipette was positioned with a micromanipulator at about 500 µm below the dorsolateral sulcus, and the injection of FluoSpheres was monitored through a surgical microscope (Li et al. 2002, 2003). After injection, the muscle and skin were sutured and the wound was closed. Animals were returned to their cages for 3–7 days, which is sufficient time to permit retrograde tracer to be transported to the PVN.
Slice preparations
A total of 46 rats were used for the electrophysiology experiments. Three to seven days after FluoSpheres injection, the rats were rapidly decapitated under halothane anaesthesia. The brain was quickly removed and placed in ice-cold artificial cerebral spinal fluid (aCSF) perfusion solution saturated with 95% O2 and 5% CO2 for 1–2 min. A tissue block containing the hypothalamus was cut from the brain and glued on to the stage of the vibratome (Technical Product International, St Louis, MO, USA), as we previously described (Li et al. 2002, 2003). Coronal slices (300 µm in thickness) containing the PVN were cut from the tissue block in ice-cold aCSF. The slices were preincubated in the aCSF, which was saturated and continuously gassed with 95% O2 and 5% CO2 at 34°C for 1 h until they were transferred to the recording chamber. The perfusion solution contained (mM): 124.0 NaCl, 3.0 KCl, 1.3 MgSO4, 2.4 CaCl2, 1.4 NaH2PO4, 10.0 glucose, and 26.0 NaHCO3. For the Ca2+-free solution, Ca2+ was replaced with an equimolar concentration of Co2+ in the perfusion solution.
Recordings of postsynaptic currents of labelled PVN neurones
Recordings of miniature postsynaptic currents were performed in a radio frequency-shielded room using the whole-cell voltage-clamp technique, as we previously described (Li et al. 2002, 2003). The recording pipettes were triple-pulled from borosilicate capillaries (1.2 mm o.d., 0.68 mm i.d.; World Precision Instruments, Sarasota, FL, USA) using a micropipette puller (P-97, Sutter Instrument, Novato, CA, USA). The resistance of the pipette was 3–5 M
when it was filled with a solution containing (mM): KCl, 140.0; MgCl2, 1.0; Hepes, 10.0; EGTA, 10.0; CaCl2, 1.0; and ATP-Mg, 2.0; adjusted to pH 7.25 with 1 M KOH (270–300 mosmol l-1). The slice was placed in a glass-bottomed recording chamber (Warner Instruments, Hamden, CT, USA) and fixed with a grid of parallel nylon threads supported by a U-shaped stainless steel weight. The slice was perfused at 3.0 ml min-1 at 34°C maintained by an in-line solution heater and a temperature controller (model TC-324, Warner Instruments). It took 
1.5 min to completely exchange the solution inside the recording chamber at the perfusion speed of 3.0 ml min-1. Whole-cell recordings from labelled PVN neurones were made under visual control using a combination of epifluoresence illumination and infrared and differential interference contrast optics on an upright microscope (BX50WI, Olympus, Japan). The labelled neurones located in the medial third of the PVN area between the third ventricle and the fornix were selected for recording. The labelled PVN neurones were briefly identified with the aid of epifluorescence illumination. The identified cell was then visualized through a camera and a video monitor using infrared and differential interference contrast optics (Fig. 1A and B). A tight giga-ohm seal was obtained by application of slight negative pressure and the cell membrane was then ruptured by further suction. Recordings of postsynaptic currents began 5 min later after the whole-cell access was established and the current reached a steady state. The input resistance was monitored, and the recording was abandoned if it changed more than 15%. Recordings were performed with an Axopatch 200B amplifier (Axon Instruments, Union City, CA, USA). Signals were filtered at 1–2 kHz, digitized at 10 kHz using Digidata 1320 A (Axon Instruments), and saved to the hard drive of a computer. At a holding potential of –70 mV and in the presence of tetrodotoxin (TTX, 1 µM) and CNQX (6-cyano-7-nitroquinoxaline-2,3-dione, 20 µM), only miniature GABAergic inhibitory postsynaptic currents (mIPSCs) are recorded in the PVN (Li et al. 2002, 2003). The miniature excitatory postsynaptic currents (mEPSCs) were recorded in the presence of TTX (1 µM) and bicuculline (20 µM).
|
Data analysis
Data are presented as means ±S.E.M. The mIPSCs and mEPSCs were analysed off-line with a peak detection program (MiniAnalysis, Synaptosoft Inc., Leonia, NJ, USA). Measurement of the amplitude and frequency and the decaying time constant of postsynaptic currents were performed for a period of 3 min during the control and drug application. The mIPSCs and mEPSCs were detected by the fast rise time of the signal over a threshold amplitude set at 6–10 pA above the background noise (Li et al. 2002, 2003). The cumulative probability of the amplitude and interevent interval of mEPSCs/mIPSCs was compared using the Kolmogorov-Smirnov test, which estimates the probability that two cumulative distributions are similar. At least 100 randomly selected mIPSCs and mEPSCs were used in each analysis. All the decay phases of mIPSCs were analysed with one and two exponential functions. Based on the curve fitting R2 values, all mIPSCs were best fitted by two components under all conditions. The effects of drugs on the amplitude and frequency of mIPSCs and mEPSCs were determined by the non-parametric Wilcoxon signed rank test or non-parametric ANOVA (Kruskal-Wallis) with Dunn's post hoc test. P < 0.05 was considered to be statistically significant.
|
Results |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
. Effect of SNAP on GABAergic mIPSCs of labelled PVN neurones
To test the effect of NO on spontaneous mIPSCs in labelled PVN neurones, an NO donor, SNAP, was used. The spontaneous mIPSCs recorded from the labelled neurones were completely abolished by bath application of 20 µM bicuculline (n= 9), the antagonist of GABAA receptors (Fig. 2A). SNAP, at a concentration of 100 µM, significantly increased the frequency of mIPSCs from 2.67 ± 0.52 to 4.98 ± 0.64 Hz without affecting the kinetics and amplitude of mIPSCs (138.6 ± 19.4 versus 140.5 ± 15.2 pA) (Fig. 2B, C and D). Neither the fast (5.89 ± 0.42 versus 6.20 ± 0.55 ms) nor slow (21.67 ± 2.02 versus 23.59 ± 1.98 ms) component of the decay phase of mIPSCs during SNAP application was significantly different from those during the control (n= 9, Fig. 2E). Repeat application of SNAP had a reproducible excitatory effect on the frequency of mIPSCs (Fig. 2C). In four separate labelled PVN neurones, 100 µM SNAP had no significant effect on the peak amplitude of electrically evoked IPSCs (300 ± 57 versus 306 ± 58 pA, P > 0.05).
|
To examine whether the SNAP-induced increase in the frequency of mIPSCs was dependent on extracellular Ca2+, the effect of SNAP on mIPSCs was tested in a Ca2+-free aCSF. In this experiment, Ca2+ was removed and replaced by an equimolar concentration of Co2+ in the perfusion solution. In eight labelled PVN cells, following testing the initial effect of SNAP (100 µM) on mIPSCs, the perfusion solution was replaced by the Ca2+-free aCSF. The frequency and the amplitude of mIPSCs was not affected by perfusion of the Ca2+-free aCSF (Fig. 3). Subsequent application of SNAP (100 µM) still significantly increased the frequency of mIPSCs in the Ca2+-free aCSF (from 2.8 ± 0.5 to 5.5 ± 0.7 Hz, P < 0.05) without affecting the amplitude of mIPSCs in these eight neurones (Fig. 3).
|
|
|
To investigate the role of cGMP in the effect of NO on synaptic GABA release to labelled PVN neurones, we tested the effect of pCPT-cGMP, a membrane-permeable analogue of cGMP, on mIPSCs. To minimize the hydrolysis of cGMP and the cGMP analogue in nerve terminals, the effect of pCPT-cGMP was examined in the presence of an inhibitor of phosphodiesterases, IBMX (100 µM) (Yawo, 1999). In the pilot experiment, pCPT-cGMP produced an inconsistent effect on mIPSCs in six cells examined in the absence of IBMX (data not shown). In the presence of 100 µM IBMX, application of 30 µM pCPT-cGMP consistently increased the frequency of mIPSCs from 2.36 ± 0.45–4.98 ± 0.56 Hz (P < 0.05) without affecting the amplitude and the decay time constant of mIPSCs in all nine neurones tested (Fig. 6). IBMX (100 µM) alone had no significant effect on the frequency and amplitude of mIPSCs (2.32 ± 0.41 to 2.38 ± 0.46 Hz, P > 0.05). The cumulative probability analysis of mIPSCs before and during pCPT-cGMP application revealed that the distribution pattern of the interevent interval of mIPSCs shifted toward the left in response to pCPT-cGMP, while the distribution pattern of the amplitude of mIPSC was not significantly changed (Fig 6B and C). The effect of pCPT-cGMP on mIPSCs was further analysed by measuring the time constant of the decay phase of spontaneous mIPSCs. Neither the fast (4.96 ± 0.39 versus 5.02 ± 0.25 ms) nor slow (18.63 ± 2.43 versus 19.45 ± 2.39 ms) component of the decay phase of mIPSCs during pCPT-cGMP application was significantly different from those during the control (Fig. 6D).
|
|
To determine whether the action of NO on mIPSCs is through activation of sGC, ODQ (10 µM), a selective inhibitor of the NO-activated sGC, was used in 11 labelled PVN neurones. Following testing the initial effect of 100 µM SNAP on mIPSCs, 10 µM ODQ was perfused into the recording chamber. In the presence of ODQ, SNAP failed to increase the frequency of mIPSCs (2.74 ± 0.75 versus 2.70 ± 0.41 Hz, P > 0.05, Fig. 8).
|
To further determine if PKG is involved in the effect of SNAP on mIPSCs, the effect of Rp-pCPT-cGMP, a specific membrane-permeable PKG inhibitor, was tested in an additional nine labelled cells. SNAP initially increased the frequency of mIPSCs from 2.87 ± 0.45 to 5.84 ± 0.65 Hz (P < 0.05, Fig. 9). However, following treatment with 1 µM Rp-pCPT-cGMP, the excitatory effect of SNAP on mIPSCs was completely abolished (2.82 ± 0.51versus2.76 ± 0.49 Hz, P > 0.05, Fig. 9).
|
|
Discussion |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
The PVN is a heterogenous region containing interneurones and many output neurones projecting to the posterior pituitary, rostral ventrolateral medulla, nucleus of the solitary tract, and intermediolateral cell column of the spinal cord (Swanson & Sawchenko, 1983; Shafton et al. 1998). Hyperactivity of PVN neurones plays an important part in the maintenance of increased sympathetic vasomotor tone in certain types of hypertension (Herzig et al. 1991; Takeda et al. 1991; Allen, 2002). Decreased GABAergic inhibition of presympathetic neurones in the PVN may be responsible for the elevated level of sympathetic outflow in hypertension (de Wardener, 2001). NO is an important inhibitory modulator in the PVN and may function as a ‘physiological brake’ to prevent over-excitation of PVN neurones and the sustained increase in sympathetic outflow (Zhang & Patel, 1998; Li et al. 2002). We have shown that NO inhibits the excitability of spinally projecting PVN neurones through potentiation of GABAergic synaptic inputs (Li et al. 2002). However, the signalling mechanisms responsible for NO-induced augmentation of GABA release to spinally projecting PVN neurones are not known. In the present study, the PVN neurones projecting to the spinal cord were identified using the retrograde labelling technique in order to specifically study this population of neurones related to the control of sympathetic efferent activity.
The neurotransmitter release from the presynaptic terminals is usually mediated through a Ca2+-dependent mechanism. It has been shown that NO-induced GABA release from cerebrocortical neurones is dependent on Ca2+ influx (Ohkuma et al. 1998). However, NO does not increase intracellular Ca2+ in cultured hippocampal neurones (Sporns & Jenkinson, 1997). Also, NO can stimulate synaptic glutamate release in the hippocampal synaptosomes, independent of Ca2+ (Meffert et al. 1994, 1996). Furthermore, a decreased presynaptic intracellular Ca2+ following exposure to NO has been reported, and the Ca2+ channel blocker, Cd2+, has no effect on NO-stimulated release of glutamate from hippocampal synaptosomes (Meffert et al. 1994). In the present study, we found that neither replacement of extracellular Ca2+ with Co2+ nor administration of Cd2+, the voltage-dependent Ca2+ channel blocker, altered the NO-induced increase in the frequency of GABAergic mIPSCs of PVN–spinal neurones. Additionally, although NO can increase the mitochondrial calcium release in neurones, its effect is not mediated by cGMP (Horn et al. 2002). In this study, we found that the effect of SNAP was persistent following treatment with thapsigargin, a Ca2+-ATPase inhibitor that depletes intracellular Ca2+ stores (Tanabe et al. 1998). Thus, these findings suggest that NO-induced increase in synaptic GABA release to spinally projecting PVN neurones is not dependent on extracellular and intracellular Ca2+ and voltage-dependent Ca2+ channels. We observed that SNAP had little effect on the peak amplitude of electrically evoked IPSCs. Unlike mIPSCs, electrically evoked IPSCs are calcium dependent (Cd2+ completely blocked evoked IPSCs, data not shown), which is different from the action of NO on spontaneous mIPSCs. Also, we have shown that NO has a general inhibitory effect on the action potential of PVN neurones (Li et al. 2002). Therefore, the observed effect of NO on synaptic GABA release to spinally projecting PVN neurones is unrelated to the action potential.
Although different mechanisms may be responsible for NO-mediated pre or postsynaptic modulation, the NO–cGMP pathways appear to be involved in the action of NO in the CNS (Stamler et al. 1997; Ahern et al. 2002). Previous studies have shown that NO–cGMP mechanisms are involved in the presynaptic modulation in the hippocampus and nucleus accumbens (Boulton et al. 1994; Kraus & Prast, 2002), but the role of cGMP in the effect of NO on synaptic neurotransmitter release remains controversial. In this regard, cGMP reduces fast glutamatergic synaptic transmission in the rat hippocampus (Boulton et al. 1994). The cGMP analogue, 8-Br-cGMP, also produces a decrease in GABA and glutamate release to magnocellular neurones in the supraoptic nucleus (Ozaki et al. 2000). On the other hand, several studies have shown that cGMP produces an excitatory effect on the neurotransmitters release. For example, NO and cGMP can facilitate glutamate and GABA release in the nucleus accumbens (Kraus & Prast, 2002). Also, NO enhances Ca2+-activated K+ channel activity by stimulating sGC and PKG, and subsequently generates a use-dependent enhancement of neurotransmitter release in posterior pituitary nerve terminals (Klyachko et al. 2001). In our study, the excitatory effect of SNAP on GABAergic mIPSCs was mimicked by a more specific membrane permeant cGMP analogue, pCPT-cGMP. However, the frequency and amplitude of glutamatergic mEPSCs were not altered by pCPT-cGMP, an effect similar to that of L-arginine and SNAP (Li et al. 2002). Furthermore, we found that the specific sGC inhibitor, ODQ, completely abolished the SNAP-induced increase in the frequency of mIPSCs. These data suggest that NO-induced potentiation of GABAergic mIPSCs is mediated by cGMP in spinally projecting PVN neurones. sGC is considered as the receptor enzyme of NO, and activation of sGC enhances the formation of cGMP (Schmidt et al. 1993). The electrophysiology data in this study strongly support the hypothesis that NO potentiates synaptic GABA release to the PVN neurones through activation of sGC and formation of cGMP in the presynaptic terminals.
There are at least three molecular targets that may mediate the action of cGMP. These include cGMP-gated ion channels (Zagotta & Siegelbaum, 1996), cGMP-dependent phosphodiesterases (Schmidt et al. 1993; Pineda et al. 1996; Kraus & Prast, 2002), and PKG (Jaffrey & Snyder, 1995). Ca2+ is the main current carrier of cGMP-gated channels (Kaupp & Seifert, 2002). In the present study, replacement of Ca2+ with Co2+ failed to attenuate NO-induced potentiation of presynaptic GABA release. Thus, cGMP-gated channels are unlikely to be involved in NO-induced GABA release in the PVN. Since pCPT-cGMP still increased the frequency of mIPSCs in the presence of a phosphodiesterase inhibitor, IBMX, this suggests that the phosphodiesterase is not involved directly in the effect of NO on synaptic GABA release to PVN neurones. In this study, IBMX was used to inhibit the phosphodiesterase, and hence to minimize the hydrolysis of pCPT-cGMP and raise the intracellular pCPT-cGMP level. The type II PKG is widely expressed on axon terminals and dendrites in the brain including the PVN (de Vente et al. 2001). In the present study, we found that the specific PKG inhibitor, Rp-pCPT-cGMP, completely eliminated SNAP-induced potentiation of mIPSCs. Therefore, these data suggest that the NO-induced increase in synaptic GABA release to PVN–spinal neurones is through PKG activation targeted by cGMP.
The potential PKG substrates involved in the action of NO on enhanced GABAergic synaptic release in the PVN are not clear. We are not aware that any vesicle protein phosphorylated by PKG is present only on GABAergic but not glutamatergic synaptic terminals. Interestingly, some studies have suggested that opioids also have a selective action on GABAergic but not glutamatergic synapses, and the voltage-gated A-type potassium channel located on the GABAergic terminals appears to be involved in the inhibitory effect of opioids on GABA release (Vaughan et al. 1997; Pan et al. 2002). It has been shown recently that stimulation of PKG inhibits the voltage-gated A-type potassium channel in neurones (Liu & Simon, 2003). However, further studies are needed to determine if the voltage-gated A-type potassium channel is the target of PKG in the PVN.
In summary, the present study provides important new information about the signalling mechanisms through which NO augments GABAergic synaptic inputs to PVN–spinal neurones. Our data suggest that NO increases synaptic GABA release to spinally projecting PVN neurones through cGMP and PKG-dependent, but Ca2+-independent, mechanisms. This new information is important to our understanding of the signal transduction mechanisms involved in the CNS action of NO in regulation of sympathetic vasomotor tone during physiological and pathological conditions.
|
References |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
Allen
AM (2002). Inhibition of the hypothalamic paraventricular nucleus in spontaneously hypertensive rats dramatically reduces sympathetic vasomotor tone. Hypertension
39, 275–280.
Boulton CL, Irving AJ, Southam E, Potier B, Garthwaite J & Collingridge GL (1994). The nitric oxide–cyclic GMP pathway and synaptic depression in rat hippocampal slices. Eur J Neurosci 6, 1528–1535.[CrossRef][Medline]
Furuyama T, Inagaki S & Takagi H (1993). Localizations of alpha 1 and beta 1 subunits of soluble guanylate cyclase in the rat brain. Brain Res Mol Brain Res 20, 335–344.[Medline]
Guevara-Guzman R, Emson PC & Kendrick KM (1994). Modulation of in vivo striatal transmitter release by nitric oxide and cyclic GMP. J Neurochem 62, 807–810.[Medline]
Herzig TC, Buchholz RA & Haywood JR (1991). Effects of paraventricular nucleus lesions on chronic renal hypertension. Am J Physiol 261, H860–867.[Medline]
Horn
TF, Wolf
G, Duffy
S, Weiss
S, Keilhoff
G
&
MacVicar
BA (2002). Nitric oxide promotes intracellular calcium release from mitochondria in striatal neurons. FASEB J
16, 1611–1622.
Imaki T, Naruse M, Harada S, Chikada N, Nakajima K, Yoshimoto T & Demura H (1998). Stress-induced changes of gene expression in the paraventricular nucleus are enhanced in spontaneously hypertensive rats. J Neuroendocrinol 10, 635–643.[CrossRef][Medline]
Jaffrey SR, Erdjument-Bromage H, Ferris CD, Tempst P & Snyder SH (2001). Protein S-nitrosylation: a physiological signal for neuronal nitric oxide. Nat Cell Biol 3, 193–197.[CrossRef][Medline]
Jaffrey SR & Snyder SH (1995). Nitric oxide: a neural messenger. Annu Rev Cell Dev Biol 11, 417–440.[CrossRef][Medline]
Kaupp
UB
&
Seifert
R (2002). Cyclic nucleotide-gated ion channels. Physiol Rev
82, 769–824.
Klyachko VA, Ahern GP & Jackson MB (2001). cGMP-mediated facilitation in nerve terminals by enhancement of the spike afterhyperpolarization. Neuron 31, 1015–1025.[CrossRef][Medline]
Kraus MM & Prast H (2002). Involvement of nitric oxide, cyclic GMP and phosphodiesterase 5 in excitatory amino acid and GABA release in the nucleus accumbens evoked by activation of the hippocampal fimbria. Neuroscience 112, 331–343.[CrossRef][Medline]
Krukoff TL (1999). Central actions of nitric oxide in regulation of autonomic functions. Brain Res Brain Res Rev 30, 52–65.[CrossRef][Medline]
Li
DP, Chen
SR
&
Pan
HL (2002). Nitric oxide inhibits spinally projecting paraventricular neurons through potentiation of presynaptic GABA release. J Neurophysiol
88, 2664–2674.
Li
DP, Chen
SR
&
Pan
HL (2003). Angiotensin II stimulates spinally projecting paraventricular neurons through presynaptic disinhibition. J Neurosci
23, 5041–5049.
Liu
L
&
Simon
SA (2003). Modulation of IA currents by capsaicin in rat trigeminal ganglion neurons. J Neurophysiol
89, 1387–1401.
Matsuoka I, Giuili G, Poyard M, Stengel D, Parma J, Guellaen G & Hanoune J (1992). Localization of adenylyl and guanylyl cyclase in rat brain by in situ hybridization: comparison with calmodulin mRNA distribution. J Neurosci 12, 3350–3360.[Abstract]
Meffert MK, Calakos NC, Scheller RH & Schulman H (1996). Nitric oxide modulates synaptic vesicle docking fusion reactions. Neuron 16, 1229–1236.[CrossRef][Medline]
Meffert MK, Premack BA & Schulman H (1994). Nitric oxide stimulates Ca(2+) -independent synaptic vesicle release. Neuron 12, 1235–1244.[CrossRef][Medline]
Ohkuma S, Katsura M, Hibino Y, Hara A, Shirotani K, Ishikawa E & Kuriyama K (1998). Mechanisms for facilitation of nitric oxide-evoked [3H]GABA release by removal of hydroxyl radical. J Neurochem 71, 1501–1510.[Medline]
Ozaki M, Shibuya I, Kabashima N, Isse T, Noguchi J, Ueta Y, Inoue Y, Shigematsu A & Yamashita H (2000). Preferential potentiation by nitric oxide of spontaneous inhibitory postsynaptic currents in rat supraoptic neurones. J Neuroendocrinol 12, 273–281.[CrossRef][Medline]
Pan
YZ, Li
DP, Chen
SR
&
Pan
HL (2002). Activation of delta-opioid receptors excites spinally projecting locus coeruleus neurons through inhibition of GABAergic inputs. J Neurophysiol
88, 2675–2683.
Pineda
J, Kogan
JH
&
Aghajanian
GK (1996). Nitric oxide and carbon monoxide activate locus coeruleus neurons through a cGMP-dependent protein kinase: involvement of a nonselective cationic channel. J Neurosci
16, 1389–1399.
Schmidt HH, Lohmann SM & Walter U (1993). The nitric oxide and cGMP signal transduction system: regulation and mechanism of action. Biochim Biophys Acta 1178, 153–175.[Medline]
Shafton AD, Ryan A & Badoer E (1998). Neurons in the hypothalamic paraventricular nucleus send collaterals to the spinal cord and to the rostral ventrolateral medulla in the rat. Brain Res 801, 239–243.[CrossRef][Medline]
Southam E & Garthwaite J (1993). The nitric oxide-cyclic GMP signalling pathway in rat brain. Neuropharmacology 32, 1267–1277.[CrossRef][Medline]
Sporns O & Jenkinson S (1997). Potassium ion- and nitric oxide-induced exocytosis from populations of hippocampal synapses during synaptic maturation in vitro. Neuroscience 80, 1057–1073.[CrossRef][Medline]
Stamler
JS, Singel
DJ
&
Loscalzo
J (1992). Biochemistry of nitric oxide and its redox-activated forms. Science
258, 1898–1902.
Stamler JS, Toone EJ, Lipton SA & Sucher NJ (1997). (S) NO signals: translocation, regulation, and a consensus motif. Neuron 18, 691–696.[CrossRef][Medline]
Swanson LW & Sawchenko PE (1983). Hypothalamic integration: organization of the paraventricular and supraoptic nuclei. Annu Rev Neurosci 6, 269–324.[CrossRef][Medline]
Takeda K, Nakata T, Takesako T, Itoh H, Hirata M, Kawasaki S, Hayashi J, Oguro M, Sasaki S & Nakagawa M (1991). Sympathetic inhibition and attenuation of spontaneous hypertension by PVN lesions in rats. Brain Res 543, 296–300.[CrossRef][Medline]
Tanabe
M, Gahwiler
BH
&
Gerber
U (1998). L-Type Ca2+ channels mediate the slow Ca2+-dependent afterhyperpolarization current in rat CA3 pyramidal cells in vitro. J Neurophysiol
80, 2268–2273.
Trabace L & Kendrick KM (2000). Nitric oxide can differentially modulate striatal neurotransmitter concentrations via soluble guanylate cyclase and peroxynitrite formation. J Neurochem 75, 1664–1674.[CrossRef][Medline]
Vaughan CW, Ingram SL, Connor MA & Christie MJ (1997). How opioids inhibit GABA-mediated neurotransmission. Nature 390, 611–614.[CrossRef][Medline]
de Vente J, Asan E, Gambaryan S, Markerink-van Ittersum M, Axer H, Gallatz K, Lohmann SM & Palkovits M (2001). Localization of cGMP-dependent protein kinase type II in rat brain. Neuroscience 108, 27–49.[CrossRef][Medline]
de Wardener
HE (2001). The hypothalamus and hypertension. Physiol Rev
81, 1599–1658.
Wood J & Garthwaite J (1994). Models of the diffusional spread of nitric oxide: implications for neural nitric oxide signalling and its pharmacological properties. Neuropharmacology 33, 1235–1244.[CrossRef][Medline]
Yang
QZ
&
Hatton
GI (1999). Nitric oxide via cGMP-dependent mechanisms increases dye coupling and excitability of rat supraoptic nucleus neurons. J Neurosci
19, 4270–4279.
Yawo
H (1999). Involvement of cGMP-dependent protein kinase in adrenergic potentiation of transmitter release from the calyx-type presynaptic terminal. J Neurosci
19, 5293–5300.
Zagotta WN & Siegelbaum SA (1996). Structure and function of cyclic nucleotide-gated channels. Annu Rev Neurosci 19, 235–263.[CrossRef][Medline]
Zhang
K, Li
YF
&
Patel
KP (2002). Reduced endogenous GABA-mediated inhibition in the PVN on renal nerve discharge in rats with heart failure. Am J Physiol Regul Integr Comp Physiol
282, R1006–1015.
Zhang K & Patel KP (1998). Effect of nitric oxide within the paraventricular nucleus on renal sympathetic nerve discharge: role of GABA. Am J Physiol 275, R728–734.[Medline]
|
Acknowledgements |
|---|
This article has been cited by other articles:
|
|
 |
|
  M. K. Kelm, H. E. Criswell, and G. R. Breese Calcium Release from Presynaptic Internal Stores Is Required for Ethanol to Increase Spontaneous {gamma}-Aminobutyric Acid Release onto Cerebellum Purkinje Neurons J. Pharmacol. Exp. Ther., October 1, 2007; 323(1): 356 - 364. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 E. Szabadits, C. Cserep, A. Ludanyi, I. Katona, J. Gracia-Llanes, T. F. Freund, and G. Nyiri Hippocampal GABAergic Synapses Possess the Molecular Machinery for Retrograde Nitric Oxide Signaling J. Neurosci., July 25, 2007; 27(30): 8101 - 8111. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Q. Chen and H.-L. Pan Signaling Mechanisms of Angiotensin II-Induced Attenuation of GABAergic Input to Hypothalamic Presympathetic Neurons J Neurophysiol, May 1, 2007; 97(5): 3279 - 3287. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Yang and C. L. Cox Modulation of Inhibitory Activity by Nitric Oxide in the Thalamus J Neurophysiol, May 1, 2007; 97(5): 3386 - 3395. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Y.-F. Li, K. L. Jackson, J. E. Stern, B. Rabeler, and K. P. Patel Interaction between glutamate and GABA systems in the integration of sympathetic outflow by the paraventricular nucleus of the hypothalamus Am J Physiol Heart Circ Physiol, December 1, 2006; 291(6): H2847 - H2856. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 H. Waki, D. Murphy, S. T. Yao, S. Kasparov, and J. F.R. Paton Endothelial NO Synthase Activity in Nucleus Tractus Solitarii Contributes to Hypertension in Spontaneously Hypertensive Rats Hypertension, October 1, 2006; 48(4): 644 - 650. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D.-P. Li, L. M. Atnip, S.-R. Chen, and H.-L. Pan Regulation of Synaptic Inputs to Paraventricular-Spinal Output Neurons by {alpha}2 Adrenergic Receptors J Neurophysiol, January 1, 2005; 93(1): 393 - 402. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D.-P. Li, S.-R. Chen, and H.-L. Pan VR1 Receptor Activation Induces Glutamate Release and Postsynaptic Firing in the Paraventricular Nucleus J Neurophysiol, September 1, 2004; 92(3): 1807 - 1816. [Abstract] [Full Text] [PDF]
|
|
| ||||||||||||||||||||||||||||||||||||
) viewed with Nomarski optics. C, photomicrograph showing the FluoSphere injection site (red) at the spinal intermediolateral cell column (IML) in one rat. Note that the bright field and fluorescence images were taken from the same tissue section and superimposed to show the location and diffusion of the FluoSphere injection. Scale bar, 50 µM in A and B; 500 µM in C. DH, dorsal horn.
fast= 4.83 ms and 
