Hydrogen sulfide increases excitability through suppression of sustained potassium channel currents of rat trigeminal ganglion neurons
- Xingmei Feng†1,
- You-Lang Zhou†2,
- Xiaowen Meng†2,
- Fei-Hu Qi3,
- Wei Chen3,
- Xinghong Jiang2 and
- Guang-Yin Xu2Email author
© Feng et al; licensee BioMed Central Ltd. 2013
Received: 28 July 2012
Accepted: 14 February 2013
Published: 18 February 2013
Hydrogen sulfide (H2S), an endogenous gaseotransmitter/modulator, is becoming appreciated that it may be involved in a wide variety of processes including inflammation and nociception. However, the role and mechanism for H2S in nociceptive processing in trigeminal ganglion (TG) neuron remains unknown. The aim of this study is to investigate distribution of endogenous H2S synthesizing enzyme cystathionine-β-synthetase (CBS) expression and role of H2S on excitability and voltage-gated potassium channels of TG neurons.
Immunofluorescence studies were carried out to determine whether CBS was co-expressed in Kv1.1 or Kv1.4-positive TG neurons. Whole cell patch clamp recordings were employed on acutely isolated TG neurons from adult male Sprague Dawley rats (6–8 week old). von Frey filaments were used to examine the pain behavioral responses in rats following injection of sodium hydrosulfide.
In rat TG, 77.3±6.6% neurons were immunoreactive for CBS, 85.1±3.8% for Kv1.1 and 97.8±1.1% for Kv1.4. Double staining showed that all CBS labeled cells were Kv1.1 and Kv1.4 positive, but only 92.2±6.1% of Kv1.1 and 78.2±9.9% of Kv1.4 positive cells contained CBS. Application of H2S donor NaHS (250 μM) led to a significant depolarization of resting membrane potential recorded from TG neurons. NaHS application also resulted in a dramatic reduction in rheobase, hyperpolarization of action potential threshold, and a significant increase in the number of action potentials evoked at 2X and 3X rheobase stimulation. Under voltage-clamp conditions, TG neurons exhibited transient A-type (IA) and sustained outward rectifier K+ currents (IK). Application of NaHS did suppress IK density while did not change IA density of TG neurons (n=6). Furthermore, NaHS, a donor of hydrogen sulfide, produced a significant reduction in escape threshold in a dose dependent manner.
These data suggest that endogenous H2S generating enzyme CBS was co-localized well with Kv1.1 and Kv1.4 in TG neurons and that H2S produces the mechanic pain and increases neuronal excitability, which might be largely mediated by suppressing IK density, thus identifying for the first time a specific molecular mechanism underlying pain and sensitization in TG.
KeywordsHydrogen sulfide Cystathionine-β-synthase Trigeminal ganglion Excitability Voltage-gated potassium channels
Hydrogen sulfide (H2S), a gas synthesized by the endogenous enzymes cystathionine-β-synthetase (CBS) and cystathionine-γ-lyase (CSE), is increasingly recognized as a biologically important signaling molecule in various tissues and pathophysiological processes including pain and inflammation [1–7]. Its putative role as a neurotransmitter is supported by recent reports on its effects on hippocampal neurons as well as peripheral sensory neurons [7–9]. With respect to the latter, intraplantar injection of NaHS (a commonly used H2S donor) in rat hindpaws produces mechanical hyperalgesia through activation of T-type Ca2+ channels , supporting a pro-nociceptive role for H2S. Further, H2S generation is also enhanced in formalin  and carrageenan  model of persistent inflammatory pain. Colonic administration of H2S enhances pain behaviors in response to CRD in mice  and rats . On the other hand, systemic injections of H2S donors in rats suppress responses to colorectal distention (CRD) by activating KATP channels , suggesting a possible anti-nociceptive effect. Although there is discrepancy, a growing body of evidence suggests that H2S plays an important effect on primary sensory neurons innervating somatic and visceral organs. However, the role of H2S on trigeminal ganglion (TG) neurons in the normal neuronal physiology remains unknown.
The aims of the present study were therefore to determine distribution of endogenous H2S synthyzing enzymes in TG neurons and to identify roles of H2S on neuronal excitability by brief exposure to NaHS, at concentrations near the reported KD values in other cellular systems. We also examined NaHS’s influence on the delayed-rectifier type of K+ currents, since such currents are an important factor in the ability of cells to fire impulses repetitively and have been identified as important parameters for the modulation of excitability by other agents, such as prostaglandin E2 and nerve growth factor . Potassium channels also have been identified as targets of drugs that relieve elevated pain. Our results show that CBS is abundantly expressed in rat TG neurons and colocalized in Kv1.1 and Kv1.4 positive neurons. H2S enhances excitability of TG neurons and suppresses IK density in vitro and reduces the escape threshold of rats.
Experiments were performed on adult male Sprague-Dawley rats (200–220 g). Care and handling of these animals were approved by the Institutional Animal Care and Use Committee at Soochow University and were in accordance with the guidelines of the International Association for the Study of Pain.
Male adult rats were deeply anesthetized with sodium pentobarbital (50 mg/kg, i.p.) and perfused transcardially with 150 mL phosphate-buffered saline (PBS) followed by 400 mL ice-cold 4% paraformaldehyde (PFA) in PBS. A pair of trigeminal ganglion was then excised and postfixed in this fixative solution and cryoprotected overnight in 20% sucrose in PBS. Ten-micrometer sections were cut in a cryostat and processed for immunofluorescence as described previously . In brief, all sections were blocked with 2% goat serum and incubated overnight at 4°C with primary antibody, followed by TRITC or FITC-conjugated secondary antibody. For double immunofluorescence, sections were simultaneously incubated with CBS (1:200, Abnova, CA) and Kv1.1 or Kv1.4 antibody (1:200, Alomone labs, Israel) and then incubated with TRITC and FITC-conjugated secondary antibody. Negative control was performed by omitting the primary antibody. Images were captured and analyzed using Metaview software (Universal Imaging Corporation Nikon, Melville, NY). To ensure that a neuron was counted only once, serial sections were placed on consecutive slides with at least 50 μm between sections on the same slide.
Temporomandibular joint (TMJ) receptive field specific TG neurons were labeled by injection of 1,19-dioleyl-3,3,39,3-tetramethy-lindocarbocyanine methanesulfonate (DiI; Invitrogen, Carlsbad, California) as described previously . In brief, animals were anesthetized with a cocktail of ketamine (80 mg/kg) and xylazine (5-10 mg/kg, intraperitoneally). The skin overlying the TMJ was shaved. The injection site was identified by palpating the zygomatic arch and mandible. DiI (25 mg in 0.5 ml methanol) was injected into both sides of TMJ skin (1 μl/site, 3 sites in each side). Multiple small injections of the tracers were made to limit the spread of the tracer into untargeted tissues . To prevent leakage, needle was left in place for 1 min for each injection. Ten days later, both TGs were dissected out for patch clamp recordings. The appearance of the injected tracer in TG neurons indicates their innervation zone in the overlying skin.
Dissociation of TG neurons
Briefly, animals were killed by cervical dislocation, followed by decapitation. A pair of TGs were then bilaterally dissected out and transferred to an ice-cold, oxygenated fresh dissecting solution, which contained (in mM): 130 NaCl, 5 KCl, 2 KH2PO4, 1.5 CaCl2, 6 MgSO4, 10 glucose, and 10 HEPES, pH 7.2 (osmolarity: 305 mOsm). After removal of connective tissue, ganglia were transferred to 5 ml of dissecting solution containing collagenase D (1.8 –2.0 mg/ml, Roche; Indianapolis, IN) and trypsin (1.2 mg/ml, Sigma; St. Louis, MO) and incubated for 1.5 h at 34.5°C. TGs were then taken from the enzyme solution, washed, and transferred to 2 ml of the dissecting solution containing DNase (0.5 mg/ml, Sigma, St. Louis, MO). A single-cell suspension was subsequently obtained by repeated trituration through flame-polished glass pipettes. Cells were plated onto acid-cleaned glass coverslips.
Coverslips containing adherent TG cells were put in a small recording chamber (0.5 ml volume) and attached to the stage of an inverting microscope (Olympus). For patch-clamp recording experiments, cells were continuously superfused (1.5 ml/ min) at room temperature with normal external solution containing (in mM) 130 NaCl, 5 KCl, 2 KH2PO4, 2.5 CaCl2, 1 MgCl2, 10 HEPES, and 10 glucose, with pH adjusted to 7.4 with NaOH (osmolarity: 295-300 mOsm). DiI-labeled neurons were identified by the bright red fluorescence in the cytoplasm. Recording pipettes were pulled from borosilicate glass tubing using a horizontal puller (P-97, Sutter Instruments) and typically had a resistance of 3.5-4.5 M when filled with normal external solution before being used immediately to obtain a gigaohm seal. Tip potential was zeroed before membrane-pipette seals were formed. The voltage was clamped at −60 mV by an EPC10 amplifier (HEKA, Germany). Capacitive transients were corrected using capacitive cancellation circuitry on the amplifier that yielded the whole cell capacitance and access resistance. Up to 80% of the series resistance was compensated electronically. Considering the peak outward current amplitudes of 10 nA, the estimated voltage errors from the uncompensated series resistance would be 10 mV. The leak currents at −60 mV were always below 20 pA and were not corrected. The action potentials and potassium currents were filtered at 2–5 kHz and sampled at 50 or 100 μs/point. Data were acquired and stored on a Dell computer for later analysis using Patch Master (HEKA, Germany). All experiments were performed at room temperature (~22°C). Only neurons with a stable initial resting potential, which drifted by less than 2–3 mV during the 10 min of baseline recording, were used in these experiments. Cells were characterized by their resting potential, input resistance, Rm. Stimulating ramps of linearly increasing current (range 0.2–0.5 nA/s) were chosen to produce more than action potentials (APs) over a 1 s depolarization for each tested neuron before and after NaHS application. In addition to the number of APs during the ramp, the AP threshold.
Isolation of Kv currents
To record KV currents, Na+ in control external solution was replaced with equimolar choline and Ca2+ concentration was reduced to 0.03 mM to suppress Ca2+ currents and to prevent Ca2+ channels becoming Na+ conducting. The reduced external Ca2+ would also be expected to suppress Ca2+-activated K+ current . The following two kinetically distinct Kv currents were isolated by the biophysical analysis and pharmacological approaches described in previous studies: IA and IK[20, 21]. IA and IK were separated biophysically by manipulating the holding potentials. The total outward currents (ITotal) were recorded in response to voltage steps from −100 to +30 mV in 5-mV increments with duration of 400 ms. IK was isolated when the membrane potential was held at −50 mV. Subtraction of IK from ITotal represented IA. To control for changes in cell size, the current density (pA/pF) was measured by dividing the current amplitude by whole cell membrane capacitance, which was obtained by reading the value for whole cell input capacitance cancellation directly from the patch-clamp amplifier.
NaHS was purchased from Sigma-Aldrich (St. Louis, MO) and was freshly prepared in normal external solution for observing RP and APs under current clamp conditions or the external solution for recording K+ current under voltage clamp conditions as described above. NaHS (250 μM) was applied directly to the recorded cell by pressure and therefore could reach equilibrium almost instantaneously. For behavioral study, NaHS (50, 250 and 1000 μM) in 50 μL was injected into the right side of the temporomandibular joint capsule, which was identified by palpating the zygomatic arch and condyle . A 30-gauge needle was inserted into the point immediately inferior to the posteroinferior border of the zygomatic arch. The needle was advanced in an anterior direction until it contacted the posterolateral aspect of the condyle. An equal volume of normal saline (NS) was used as control.
Mechanical threshold for escape behavior
Mechanical hyperalgesia was measured by a previously described protocol with some minor modifications [22, 23]. Rats were weighed and placed individually in small plastic cages and allowed to adapt to the observation cage and to the testing environment for over 1 h. During this period, the experimenter reached slowly into the cage to touch the walls of the cage with a plastic rod. After the rats were habituated to the reaching movements, the series of mechanical stimulations were started. The virissas were carefully shaved and the ipsilateral and contralateral facial skin regions were tested. The mechanical response threshold of escape behavior was measured before and after injection of NaHS or NS. A graded series of von Frey filaments were used. The filaments produced a bending force of 0.55, 0.93, 1.61, 1.98, 2.74, 4.87, 7.37, 11.42, 15.76, 20.30, and 38.69 g. The response was observed to belong to one or one more of the following responses: 1) the rat turns the head slowly away or moves it briskly backward when the stimulation is applied, and sometimes a single face wipe ipsilateral to the stimulated area occurs; 2) the rat avoids further contact with the stimulus object, either passively by moving its body away from the stimulating object to assume a crouching position against the cage wall, or actively by attacking the stimulus object, making biting and grabbing movements; 3) the rat displays an uninterrupted series of at least three face-wash strokes directed toward the stimulated facial area. Each filament was tested three times at an interval of 30 seconds. If response was observed at least two times after probing with a filament, the rats were considered responsive to that filament. The response threshold was defined as the minimum intensity for eliciting the response according to the method described by Chaplan and collaborator .
All values are given as mean±SEM. No neuron with a resting membrane potential more depolarized than −40 mV was included in the data analysis. Statistical significance was determined by one-way ANOVA or Student’s t-test or Fisher’s exact test, as appropriate. p<0.05 was considered statistically significant.
CBS is abundantly expressed by TG neurons
CBS is co-localized with Kv1.1 and Kv1.4 in TG neurons
Distribution of CBS and K v 1.1 or K v 1.4 in TG neurons
% of CBS position neurons
% of Kv1.1 position neurons
% of Kv1.4 position neurons
% of Kv1.1 position neurons
% of Kv1.4 position neurons
NaHS depolarizes resting membrane potentials
NaHS increases excitability of TG neurons
To further compare numbers of AP firing of TG neurons before and after NaHS application, we also used 1 second ramp current injections from 0 pA to 200 pA or 500 pA (Figure 3C & D). Because APs elicited by ramp current injection showed adaptation in some neurons, we counted only overshooting APs (i.e., AP with peak >0 mV). The average numbers of APs before NaHS application were 9.0±2.1 and 12.1±2.2 for 200 pA and 500 pA, respectively. After NaHS (250 μM) application, the average numbers of APs were 11.9±2.0 and 16.1±1.9 for 200 pA and 500 pA, respectively. The use of NaHS significantly enhanced the number of APs evoked by 200 or 500 pA current injection.
NaHS suppresses IK density of TG neurons
NaHS produces mechanical hyperalgesia
Our study demonstrates for the first time that endogenous H2S producing enzyme cystathionine β-synthase (CBS) is abundantly expressed by trigeminal ganglion neurons and co-localized in Kv1.1 and Kv1.4 positive neurons (Figure 1). CBS and systathionine γ-lyase (CSE) are two important endogenous enzymes for generation of H2S in mammals, and have been found in many types of mammalian cells in the central nervous system as well as in the peripheral tissues [28–30]. We have previously reported that CBS was predominately expressed by small and medium sized dorsal root ganglion neurons and co-localized well with purinergic P2X3 receptors and TRPV1 in colon specific neurons, suggesting a role for CBS in visceral hypersensitivity . In this study, we showed that administration of NaHS, which mimics CBS production of H2S, reduced mechanical escape threshold in a dose-dependent manner (Figure 5), indicating that endogenous CBS-H2S signaling pathway might be involved in the trigeminal nociceptive processing.
H2S, formed by these two enzymes, has been found to regulate key neuronal functions, including induction of long-term potentiation and modulation of NMDA receptor currents in the hippocampus under physiological conditions . In addition, H2S donor NaHS enhanced the excitability of dorsal root ganglion neurons in vitro. In this study, we provide direct evidence that H2S donor NaHS sensitized TG neurons. This conclusion is based on several findings shown in Figures 2 and 3. First, NaHS application led to a marked depolarization of RP of TG neurons (Figure 2B). Secondly, these neurons exhibited lower current thresholds for initiating an action potential (AP, Figure 2C) and lower AP thresholds (Figure 2D). Finally, these neurons had an enhanced firing frequency in response to a standardized current stimulation after NaHS application (Figure 3). Together with our previous report that H2S enhanced the neuronal excitability of colon-specific DRG neurons , the present study indicates that H2S modulates membrane properties of rat primary sensory neurons.
Another interesting finding is that NaHS application significantly suppressed IK density in TG neurons (Figure 4). To the best of our knowledge, it is the first report that H2S play an inhibitory effect on voltage-gated potassium channels of TG neurons. At least 6 types of K+ currents have been detected in sensory neurons; including both rapidly inactivating, A-type K+ currents (IA) and slow-inactivating sustained (K-current; IK) [20, 21], and several different isoforms of K+ currents with different kinetics, and their related protein subunits, have been identified in primary sensory neurons. These voltage-gated K+ (Kv) channels are important physiological regulators of membrane potentials, action potential shape and firing frequencies in nociceptive sensory neurons and often shown to be decreased during injury-induced hyperalgesia [33, 34]. Since the opening of K+ channels leads to hyperpolarization of cell membrane and a consequent decrease in neuronal excitability , the reduction in IK density induced by NaHS may well contribute to the enhanced excitability of TG neurons. Although we do not know the intracellular pathway(s) for these effects of H2S, the acute inhibition of channel activity would likely explain these effects. However, other possibilities such as regulation of protein trafficking or endocytosis cannot be excluded. In addition, amplification of TRPV1 currents by H2S occurs via releasing tachykinins , and if this is also the pathway for H2S’s modulation of IK, then H2S acts on different receptors to activate separate intracellular pathways that converge on common targets. Their combined actions in the setting of peripheral tissue injury or inflammation probably ensures a strong, acute and prolonged response in nociceptor firing. When added to the amplified response of TRPV1 or purinergic receptors caused by H2S, and possibly others, e.g., nerve growth factors, the net effect will integrate a heightened transduction of nociceptive stimuli with reduced threshold and elevated repetitive firing to produce a powerful sensitization of TG nociceptors. Of note is that we do not know whether extracellular or intracellular or both sides of H2S mediate the modulation of potassium channels since H2S are membrane permeable. Future studies are needed to investigate the detailed mechanisms.
In addition to the effect of IK, the contribution of other K+ channels to the enhanced excitability of TG neurons has also to be considered. Transient K+ currents (IA) have been reported to be one of the major players in control of neuronal excitability . In this study, however, NaHS incubation had no effect on IA, indicating a specific effect of H2S. TG neurons after NaHS application depolarized resting membrane potentials without changes in membrane input resistance. Changes in RP may be mediated by modulation of hyperpolarization-activated cation current (IH; an inwardly rectifying current)  or leakage current (IL; an outward resting current) . However, the depolarization of RP in our study is unlikely due to an increase in IH, as this would be expected to result in a decrease in input resistance. Thus, depolarization of RPs in TG neurons after NaHS application may likely have resulted from a decrease in IL. However, in our experiments, when the RPs of TG neurons were corrected to the normal level (i.e., -55 mV) after NaHS application, the rheobase and cell spike frequency were not significantly changed compared with those before the correction of RPs (data not shown). Thus, even if there were changes in IL, they had a minimal effect on spike frequency and current threshold in this study. At this time we cannot rule out the possibility that H2S modulates other voltage-gated ion channels, including NaV and the various Ca2+ channels. Previous studies have shown that NaHS/H2S activates or sensitizes Cav3.2 T-type Ca2+ channels expressed in the primary afferents  and TRPV1 and TRPA1 in nonvascular smooth muscles . H2S is now thought to join the set of agents that enhance excitability; it too enhances TRPV1 currents and suppresses IK. These combined changes in the activities of different ion channels will have a strong, possibly synergistic effect in enhancing excitability, particularly for inducing repetitive firings to produce a powerful sensitization of TG nociceptors under pathophysiological conditions such as TMJ inflammation.
In conclusion, our data demonstrate that H2S enhanced the neuronal excitability and suppressed the IA potassium current density, indicating that CBS-H2S signaling pathways may play a role in trigeminal physiology and pathophysiology. Previous studies in different trigeminal nerve inflammation/injury models suggested that the hyperexcitability of primary afferent neurons contributes to the hyperalgesia and allodynia. Further experiments are warranted to determine changes in CBS-H2S signaling under chronic pain conditions such as temporomandibular joint and related disorders.
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