Modulation of transient receptor potential vanilloid 4-mediated membrane currents and synaptic transmission by protein kinase C
© Cao et al; licensee BioMed Central Ltd. 2009
Received: 23 December 2008
Accepted: 10 February 2009
Published: 10 February 2009
Transient receptor potential Vanilloid (TRPV) receptors are involved in nociception and are expressed predominantly in sensory neurons. TRPV1, a non-selective cation channel has been extensively studied and is responsible for inflammatory thermal hypersensitivity. In this study, the expression and function of TRPV4 have been characterized and compared with those of TRPV1.
Immunohistochemical studies revealed that both TRPV1 and TRPV4 were co-expressed in dorsal root ganglion (DRG) neuronal cell bodies and in the central terminals of laminae I and II of the spinal dorsal horn (DH). In Ca2+ fluorescence imaging and whole-cell patch-clamp experiments, TRPV1- and TRPV4-mediated responses were observed in a population of the same DRG neurons. Sensitization of TRPV1 has been shown to be involved in inflammatory pain conditions. Incubation with phorbol 12, 13-dibutyrate (PDBu), a PKC activator, resulted in a significant potentiation of TRPV4 currents in DRG neurons. In TRPV4 expressing HEK 293T cells, PDBu increased 4α-phorbol 12, 13-didecanoate (4α-PDD)-induced single-channel activity in cell-attached patches, which was abrogated by bisindolylmaleimide (BIM), a selective PKC inhibitor. TRPV4 is also expressed at the central terminals of sensory neurons. Activation of TRPV4 by 4α-PDD increased the frequency of miniature excitatory post synaptic currents (mEPSCs) in DRG-DH neuronal co-cultures. 4α-PDD-induced increase in the frequency of mEPSCs was further enhanced by PDBu. The expression of TRP channels has been shown in other areas of the CNS; application of 4α-PDD significantly increased the mEPSC frequency in cultured hippocampal neurons, which was further potentiated by PDBu, whereas, TRPV1 agonist capsaicin did not modulate synaptic transmission.
These results indicate that TRPV4 and TRPV1 are co-expressed in certain DRG neurons and TRPV4 can be sensitized by PKC not only in DRG neuronal cell bodies, but also in the central sensory and non-sensory nerve terminals. Co-expression of TRPV1 and TRPV4 ion channels, their modulation of synaptic transmission and their sensitization by PKC may synergistically play a role in nociception.
Transient receptor potential (TRP) channels are involved in initiating and transmitting sensory information from the periphery to the CNS. TRPV4 is a Ca2+ permeable non-selective cation channel, first described as an osmosensor  and recently has been shown to be activated by heat (> 27°C), low pH, phorbol ester derivative 4α-phorbol 12, 13-didecanoate (4α-PDD), endocannabinoids and arachidonic acid (AA) metabolites [2–6]. It is expressed in multiple tissues, including lung, kidney, heart, gut, sensory neurons, sympathetic neurons, vascular smooth muscle cells and endothelial cells [1, 2, 7–9]. The higher expression levels of TRPV4 in keratinocytes indicate that contribution of TRPV4 to thermal sensation is not restricted to sensory neurons . TRPV4 null mice displayed impaired osmotic regulation, suggesting that TRPV4 is necessary for maintaining osmotic equilibrium in mammals . It has been reported that inflammatory and thermal hyperalgesia induced by carrageenan is attenuated in TRPV4 knockout mice . TRPV4 has been shown to be required for hypotonicity-induced nociception and chemotherapy-induced neuropathic pain [13, 14]. Furthermore, in models of painful peripheral neuropathy induced by vincristine chemotherapy, alcoholism and diabetes, mechanical hyperalgesia was attenuated by intrathecal injection of TRPV4 antisense oligodeoxynucleotides, and the similar effect was also observed in TRPV4 knockout mice . TRPV4 deficient mice exhibited impaired acid- and pressure-induced nociception . TRPV4 has been shown to contribute to visceral hypersensitivity [16, 17]. These studies suggest that TRPV4 is involved in both inflammatory and neuropathic pain and play a key role in mechanical nociception.
Vascular endothelial cells, renal collecting duct cells and vascular smooth muscle cells expressing TRPV4 are particularly susceptible to cell swelling-induced Ca2+ influx that can be blocked by ruthenium red, a nonspecific blocker of TRP channels [4, 7, 18, 19]. Cell swelling also activates phospholipase A2 (PLA2) and produces AA. AA and its cytochrome P450 metabolite 5',6'-epoxyeicosatrienoic acids (EETs) activate TRPV4 . Further evidence for this pathway is shown by the ability of PLA2 blockers to inhibit hypotonicity-induced Ca2+ influx and membrane current . In behavioral studies, hypotonicity-induced nociception has been shown to involve PKA- and/or PKC-mediated phosphorylation . Modulation of TRPV1 by PKC has been extensively studied; in this study, we will address the modulation of 4α-PDD-induced TRPV4 function by PKC.
Activation of TRPV1 modulates synaptic transmission at the first sensory synapse between DRG and DH neurons [22–25]. TRPV1 has also been reported to modulate synaptic transmission in certain regions of the brain [26–29]. The activation of TRPV4 facilitated substance P (SP) and calcitonin gene related peptide (CGRP) release from the central terminals of primary neurons in the spinal cord . Although it has been demonstrated that TRPV4 is expressed in sensory and non-sensory neurons, the role of TRPV4 in the modulation of synaptic transmission remains to be studied.
In this study, we show that TRPV4 is co-expressed with TRPV1 in DRG and dorsal horn laminae I and II. We have also found that TRPV4-mediated channel activity induced by 4α-PDD is further augmented by activation of PKC. In addition, TRPV4 activation modulates synaptic transmission in DRG-DH co-cultures and hippocampal neuronal cultures, which is further enhanced by the activation of PKC.
Five weeks old Sprague-Dawley rats were anesthetized by isoflurane and perfused with 4% paraformaldehyde. Samples of lumbar segments of the spinal cord and DRG were harvested and quickly frozen. The spinal cord and DRG were cut into 20 and 10 μm sections, respectively. The sections were incubated with polyclonal goat anti-TRPV1 antibody (Calbiochem, PC 420, 1:100) and rabbit anti-TRPV4 antibody (Alomone, Israel, 1:100) for 2 hrs at room temperature, then incubated with Rhodamine Red ™-X donkey anti-goat IgG (Jackson, 711-295-152, 1: 100) and FITC donkey anti-rabbit IgG (Jackson, 715-095-151, 1: 100) for 1 hr at room temperature. Images were taken by a confocal microscope.
DRG, DRG-DH and hippocampal neuronal cultures
DRG, DH and hippocampal neurons were isolated from embryonic day 18 (E18) rat embryos, triturated and cultured in Neurobasal medium (Invitrogen, Carlsbad, CA). The adult DRG neurons were dissociated from 5 weeks old rats. The serum-free medium was supplemented with B-27 and glutamine (Gibco Invitrogen, Grand Island, NY) and the neurons were plated on poly-D-lysine-coated glass coverslips. The neurons were used after 2 weeks growth in culture.
HEK 293T cell culture and transfection
Human embryonic kidney 293T cells were cultured in DMEM with 10% fetal bovine serum and penicillin (50 units/ml)-streptomycin (25 μg/ml) (Gibco Invitrogen, Grand Island, NY). TRPV4 cDNA and GFP cDNA were co-transfected into HEK 293T cells with Lipofectamine 2000 reagent following manufacture's protocol (Invitrogen, Carlsbad, CA). The fluorescent cells were used for recording currents 24 hrs after transfection. The non-fluorescent cells were used as a negative control.
Ca2+ fluorescence imaging
Adult dissociated rat DRG neurons plated on glass coverslips were incubated with 3 μM Fluo-4 AM (Invitrogen, Eugene, OR) for 30 min at 37°C and washed with physiological buffer containing the following (in mM): 140 NaCl, 5 HEPES, 2 CaCl2, 1 MgCl2, 2.5 KCl, 2 Lidocaine, pH 7.35. Fluo-4 was excited at 488 nm, and emitted fluorescence was filtered with a 535 ± 25 nm bandpass filter. The ratio of the fluorescence change F/F o was plotted to represent the change in intracellular Ca2+ levels.
Whole-cell current recording
DRG neurons grown on poly-D-lysine-coated coverslips were used for recording TRPV1 and TRPV4 currents. For whole-cell patch-clamp recordings, the bath solution contained (in mM): 140 Na gluconate, 5 KCl, 10 HEPES, 1 MgCl2, 1.5 EGTA, pH adjusted to 7.35 with NaOH and the pipette solution contained (in mM): 140 K gluconate, 5 KCl, 10 HEPES, 2 MgCl2, 10 EGTA, 2 K2ATP, 0.5 GTP, pH adjusted to 7.35 with KOH. Currents were recorded using an Axopatch 200B integrating patch-clamp amplifier (Axon Instruments Inc., Union City, CA). Data were digitized (VR-10B; InstruTech, Great Neck, NY) and stored on videotape. For analysis, data were filtered at 2.5 kHz (-3 dB frequency with an eight-pole low-pass Bessel filter; LPF-8; Warner Instruments, Hamden, CT) and digitized at 5 kHz. Current amplitudes were measured using Channel 2 (software kindly provided by Michael Smith, Australian National University, Canberra, Australia).
Single-channel current recording
The cell-attached patch-clamp technique was used to record single-channel currents. The bath solution contained (mM): K gluconate 140, KCl 2.5, MgCl2 1, HEPES 5, EGTA 1.5, pH adjusted with KOH to 7.3. The patch pipettes were made from glass capillaries (Drummond, Microcaps), coated with Sylgard (Dow Corning, Midland, MI, USA). The patch pipettes were filled with a solution that contained (mM): Na gluconate 140, MgCl2 2, HEPES 10, EGTA 1, pH adjusted with NaOH to 7.35. Currents were recorded using an Axopatch 200B integrating patch-clamp amplifier (Axon Instruments Inc., Union City, CA). Data were digitized (VR-10B; InstruTech, Great Neck, NY) and stored on videotape. For analysis, data were filtered at 10 kHz (-3 dB frequency with an eight-pole low-pass Bessel filter; LPF-8; Warner Instruments, Hamden, CT) and digitized at 50 kHz. The data were analyzed using Channel 2 and QUB (State University of New York at Buffalo, NY)
Synaptic current recording
DRG, DH and hippocampal pyramidal neurons were identified by their morphology. The extracellular bath solution contained (in mM): 130 NaCl, 5 KCl, 1 MgCl2, 1 CaCl2, 10 HEPES, 5 D-glucose, pH 7.35 and the pipette solution contained (in mM): 140 K gluconate, 2 MgCl2, 1 EGTA, 10 HEPES, 1 ATP, pH adjusted to 7.35 with KOH. In order to record fast excitatory postsynaptic currents, neurons were voltage-clamped (Axopatch 200B, Axon Instruments Inc., Union City, CA) at -60 mV (close to ECl). While recording mEPSCs the bath solution contained lidocaine (10 mM). The data were filtered at 2.5 kHz and digitized at 5 kHz. Data were analyzed using Mini Analysis Program (Synaptosoft, Decatur, GA). The amplitude and frequency of the events were determined from 30 s data segments.
Chemicals and reagents
B27, glutamine, fetal bovine serum and penicillin-streptomycin were obtained from Gibco Invitrogen, Grand Island, NY. Fluo-4 AM was obtained from Invitrogen, Eugene, OR. Lipofectamine 2000 reagent was obtained from Invitrogen, Carlsbad, CA. All other chemicals used in this study were obtained from Sigma (St. Louis, MO).
Data are represented as mean ± S. E. M. (Standard Error of the Mean) Kolmogorov-Smirnov (KS) test was used to compare the cumulative probability for inter-events and amplitude between different groups. Student's t-test and one way analysis of variance (ANOVA) were used for statistical comparisons and the significance is considered at P < 0.05.
Expression and co-expression of TRPV4 in DRG neurons
Then, we used whole-cell current recordings and determined whether TRPV1- and TRPV4-mediated currents can be elicited in the same neuron. In embryonic rat DRG neuronal cultures, 51/73 neurons responded to both capsaicin (100 nM) and 4α-PDD (10 μM) (Fig. 1G). These results indicate that TRPV1 and TRPV4 are co-expressed in DRG neurons. A higher number of neurons co-expressing TRPV1 and TRPV4 in whole-cell current recording as compared to immunostaining or Ca2+ fluorescence imaging techniques may be due to the bias of selecting small diameter neurons or differential expression of these two channels between embryonic and adult DRG neurons.
Modulation of TRPV4 by PKC
Several TRP channels have been shown to be modulated by PKC, which contributes to inflammatory pain . There are suggestions that TRPV4 may be modulated/activated by PKC [32, 33]. In order to determine the modulation of 4α-PDD-induced TRPV4 currents by PKC, we used patch-clamp technique and recorded whole-cell and single-channel currents.
In order to determine voltage dependency of the channel activity, we analyzed single-channel open probability at different membrane potentials from apparent single-channel patches. Single-channel patches were confirmed in patches that exhibited high Po by using the criteria of non-overlapping events when the Po was > 0.7. The Po at +60 mV and -60 mV is 0.84 ± 0.11 and 0.57 ± 0.11 (n = 3) in DRG neurons and 0.14 ± 0.04 and 0.07 ± 0.03 (n = 4) in HEK cells expressing TRPV4, respectively. These studies suggest that TRPV4 exhibits a milder voltage dependency in Po as compared to TRPV1.
Role of TRPV4 expressed in the central terminals of the spinal cord
Modulation of synaptic transmission by 4α-PDD in hippocampal neurons
TRPV1 has been extensively studied and has been shown to be involved in inflammatory thermal hypersensitivity. In this study, we have shown that: 1) TRPV1 and TRPV4 are co-expressed in a population of DRG neurons and their terminals in spinal dorsal horn; 2) TRPV4 can be sensitized by activation of PKC in DRG neurons similar to that of TRPV1; 3) Activation of TRPV4 modulates synaptic transmission at the first sensory synapse in the spinal cord, which is enhanced by activation of PKC similar to that of TRPV1; 4) TRPV4, but not TRPV1 activation modulates synaptic transmission between hippocampal neurons.
TRPV4 has been demonstrated to be activated by heat (> 27°C) and TRPV4-mediated Ca2+ influx is strongly enhanced at 37°C in a PKC-dependent and -independent manner [2, 33]. PKC activation by phorbol ester derivatives induced Ca2+ influx in HEK 293 cells transfected with human TRPV4 cDNA and exposure to a hypotonic solution after phorbol myristate acetate incubation further increased intracellular Ca2+ . Furthermore, Alessandri-Haber et al. reported that hypotonicity-induced Ca2+ influx was reduced by a PKCε inhibitor in DRG neurons .
We have conducted experiments at room temperature to avoid temperature effects and have studied whether 4α-PDD-induced TRPV4 responses could be modulated by activation of PKC. We have found that 4α-PDD-induced TRPV4 channel activity is further potentiated by PKC in whole-cell and single-channel recordings from DRG neurons and HEK cells expressing TRPV4. The results suggest that phosphorylation of TRPV4 by PKC is capable of sensitizing this channel. Single-channel recordings show that the potentiation is due to an increase in the open probability. Our study shows that a population of DRG neurons co-expresses both TRPV1 and TRPV4. TRPV1 has been implicated to contribute to inflammatory thermal and chemical pain [44, 45]. Given the finding that TRPV4 contributes to mechanical hyperalgesia in behavioral tests and TRPV1 is involved in inflammatory thermal hyperalgesia, expression of both of these channels in one neuron will synergistically modulate nociception.
A hall-mark characteristic of many TRP channels is outward rectification. We have shown that the outward rectification observed with TRPV1 channels is due to both reduced single-channel conductance and open probability at negative potentials . Single-channel TRPV4 currents recorded from DRG neurons showed more pronounced outward rectification as compared to currents recorded from HEK cells. This may be due to associated channel protein such as PACSIN3 .
The synaptic transmission between DRG neurons and spinal DH neurons play a key role in pain processing. Glutamate is released from presynaptic terminal (the central terminal of DRG neurons) upon a variety of stimuli and binds to its postsynaptic receptors (NMDA and AMPA receptors). Any process that increases glutamate release (presynaptic effect) or augments AMPA and NMDA receptor function (postsynaptic effect) may underlie central sensitization. Application of 4α-PDD significantly increased the frequency of mEPSCs without affecting the amplitude suggests that synaptic transmission is modulated by a presynaptic locus of action. This is expected because in the spinal cord TRPV4 is expressed only at the central sensory nerve terminals. However, one could also envision a postsynaptic effect by the release of neuropeptides such as CGRP, SP and bradykinin during intense synaptic activity. It has been shown that activation of PKC by PDBu or diacylglycerol (DAG) enhances excitatory synaptic transmission in the hippocampus [37–40]. Munc 13-1 is an essential priming factor in synaptic vesicles and it has a DAG/PDBu binding C1 domain [40, 46]. Munc 18-1 has been shown to be essential for presynaptic vesicle release and has been identified as a PKC substrate . Activation of Munc 13-1 or Munc 18-1 results in synaptic vesicle release. These studies suggest that PDBu-induced potentiation of synaptic transmission can be both PKC-dependent and PKC-independent mechanisms . Although PDBu can modulate synaptic transmission by itself, we observed that activation of TRPV4 and PKC, synergistically increased the frequency of mEPSCs as shown with TRPV1 . Therefore, enhanced expression and function of TRPV4 will result in increased excitability of spinal dorsal horn neurons, which may contribute to central sensitization. In disease conditions such as diabetes, the expression and function of TRPV1 is altered in spinal dorsal horn . Similarly, TRPV4 expression and function could be altered in disease conditions. The endogenous ligand for TRPV4 may be EETs, generated from AA by cytochrome P450 epoxygenase activation during cell swelling . It has been shown that intrathecal administration of TRPV4 antisense oligonucleotides reduces mechanical hyperalgesia . However, it is not clear the locus of action of the antisense oligonucleotides. Furthermore, centrally acting TRPV1 antagonist has been shown to be more effective , raising the possibility that antagonizing the central TRPs contributes to the overall analgesic action. Therefore, targeting TRPV4 at the central terminals may be a useful strategy to combat certain modalities of pain.
TRP channels are expressed in different regions of the brain. Both TRPV1 and TRPV4 are expressed in the hippocampus [41, 43, 51]. TRPV1 activation has been reported to be involved in augmentation of synaptic transmission in the hypothalamus, locus coeruleus, nucleus tractus solitarius, substantia nigra and spinal cord by the observation that the mEPSC frequency was enhanced following application of capsaicin [22, 23, 25–28, 52, 53]. Furthermore, in hippocampal interneurons, TRPV1 activation has been shown to mediate a form of LTD involving interneurons, which is absent in TPRV1 knockout mice. LTD was induced by the TRPV1 agonists and inhibited by TRPV1 antagonists . TRPV1 knockout mice show reduced anxiety-related behavior and deficits in developing long-term potentiation . In this study, we show that activation of TRPV4, but not TRPV1, modulates synaptic transmission in voltage-clamped cultured pyramidal hippocampal neurons, suggesting that TRPV4 might play a role in CNS function. TRPV1-mediated membrane currents in hippocampal neurons have not been characterized fully. Therefore, lack of TRPV1-mediated response in our experiments is possibly due to rapid desensitization of TRPV1, selective expression in specific neurons or ontogenic expression (embryonic vs. adult). Future experiments conducted on specific cell types and from embryonic vs. adult neurons may resolve this discrepancy.
This study indicates that TRPV1 and TRPV4 are co-expressed in certain DRG neurons and TRPV4 can be sensitized by PKC not only in DRG neuronal cell bodies, but also in the central sensory and non-sensory nerve terminals. Co-expression of TRPV1 and TRPV4 ion channels, their modulation of synaptic transmission and their sensitization by PKC may synergistically play a role in nociception.
This work was supported by a grant from NIH (DK065742) and SIU Excellence in Academic Medicine grant to L.S.P. The TRPV1 cDNA was kindly provided by David Julius. The TRPV4 cDNA was kindly provided by Wolfgang Liedtke. The hippocampal cultures were kindly provided by Gregory Brewer.
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