Contribution of TRPC3 to store-operated calcium entry and inflammatory transductions in primary nociceptors
© Alkhani et al.; licensee BioMed Central Ltd. 2014
Received: 26 November 2013
Accepted: 9 June 2014
Published: 26 June 2014
Prolonged intracellular calcium elevation contributes to sensitization of nociceptors and chronic pain in inflammatory conditions. The underlying molecular mechanisms remain unknown but store-operated calcium entry (SOCE) components participate in calcium homeostasis, potentially playing a significant role in chronic pain pathologies. Most G protein-coupled receptors activated by inflammatory mediators trigger calcium-dependent signaling pathways and stimulate SOCE in primary afferents. The aim of the present study was to investigate the role of TRPC3, a calcium-permeable non-selective cation channel coupled to phospholipase C and highly expressed in DRG, as a link between activation of pro-inflammatory metabotropic receptors and SOCE in nociceptive pathways.
Using in situ hybridization, we determined that TRPC3 and TRPC1 constitute the major TRPC subunits expressed in adult rat DRG. TRPC3 was found localized exclusively in small and medium diameter sensory neurons. Heterologous overexpression of TRPC3 channel subunits in cultured primary DRG neurons evoked a significant increase of Gd3+-sensitive SOCE following thapsigargin-induced calcium store depletion. Conversely, using the same calcium add-back protocol, knockdown of endogenous TRPC3 with shRNA-mediated interference or pharmacological inhibition with the selective TRPC3 antagonist Pyr10 induced a substantial decrease of SOCE, indicating a significant role of TRPC3 in SOCE in DRG nociceptors. Activation of P2Y2 purinoceptors or PAR2 protease receptors triggered a strong increase in intracellular calcium in conditions of TRPC3 overexpression. Additionally, knockdown of native TRPC3 or its selective pharmacological blockade suppressed UTP- or PAR2 agonist-evoked calcium responses as well as sensitization of DRG neurons. These data show a robust link between activation of pro-inflammatory receptors and calcium homeostasis through TRPC3-containing channels operating both in receptor- and store-operated mode.
Our findings highlight a major contribution of TRPC3 to neuronal calcium homeostasis in somatosensory pathways based on the unique ability of these cation channels to engage in both SOCE and receptor-operated calcium influx. This is the first evidence for TRPC3 as a SOCE component in DRG neurons. The flexible role of TRPC3 in calcium signaling as well as its functional coupling to pro-inflammatory metabotropic receptors involved in peripheral sensitization makes it a potential target for therapeutic strategies in chronic pain conditions.
The transient receptor potential (TRP) gene superfamily consists of a large set of tetrameric channels permeable to monovalent and/or divalent cations. In mammals, several of the 28 TRP channel family members are expressed in subpopulations of peripheral sensory neurons and are involved in the transduction of thermal, mechanical and chemical stimuli, with documented roles in normal and pathological nociception .
However, both the cellular physiology of TRP canonical (TRPC) channels in sensory neurons and their exact role in nociception have yet to be clarified. The TRPC subtypes are non-selective calcium-permeable cationic channels ubiquitously expressed in most tissues. They integrate several types of intracellular stimuli, including PLC and PKC activity, DAG levels, intracellular calcium levels and PIP2 levels into changes in membrane potential and calcium entry . Of particular interest is the role of TRPC3 in somatosensory pathways because of recent evidence pointing to an almost exclusive expression of this channel in IB4+ nociceptors, a large population of C-fiber nonpeptidergic sensory neurons known to contribute to inflammatory pain .
One of the hallmarks of inflammatory pain is the sensitization of peripheral nociceptors innervating the inflamed area. During the inflammation process, induced either by chemical agents, injury or infection, a stimulus-response shift is observed in nociceptors, resulting in an enhanced response to noxious stimuli (hyperalgesia) or in a nocifensive response to normally innocuous stimuli (allodynia) . The many chemicals released at the site of inflammation form a “soup” that triggers oedema, itchiness, redness, and sensitization . This “inflammatory soup” consists of a diverse set of signaling molecules which are capable of inducing hyperexcitability by activating their cognate membrane receptors at the surface of nociceptors . Many of these receptors include well characterized Gq-protein coupled receptors (GqPCR), such as the P2Y2 purinoceptor, bradykinin B2 and protease-activated PAR2 receptor [6, 7]. The coupling of these GqPCRs to the phospholipase C (PLC) pathway produces two bioactive compounds upon stimulation, diacylglycerol (DAG) and inositol trisphosphate (IP3), both of which act to increase intracellular calcium levels through two distinct mechanisms: one is referred to as store-operated calcium entry (SOCE) and involves the activation of calcium channels by IP3-induced depletion of endoplasmic reticulum calcium stores. The other, receptor-operated calcium entry (ROCE), involves the activation of calcium-permeable channels directly by DAG [8–11]. Hence, the production of these two secondary messengers via PLC activation results in both intracellular calcium levels increase and enhanced entry of extracellular calcium across the plasma membrane following depletion of calcium stores. Crucially, one common resulting action of these two pathways is the downstream activation of calcium-dependent protein kinase C (PKC) isoforms mediating the phosphorylation and sensitization of voltage- and ligand-gated channels involved in acute and chronic inflammatory responses [12, 13].
The signaling pathways of known pro-inflammatory receptors in DRG neurons such as P2Y2 and PAR2 are not completely characterized, but an increase in intracellular calcium levels is critical for the activation of their downstream effectors [8, 10, 14]. It has recently been shown that an abnormal persistent increase in intracellular calcium levels mediates the transition from acute to chronic pain in inflammatory pancreatitis [15, 16]. Thus the regulation of intracellular calcium levels, primarily through SOCE, could be a key mechanism in preventing sensitization. While most TRPC channel subtypes play a role in ROCE, some members of the TRPC family have been implicated in SOCE signaling as well [17, 18]. Moreover, members of the TRPC3/6/7 channel subfamily have been shown to be functionally coupled to the PLC pathway in various mammalian cell lines [19–22]. In addition, TRPC channels have been linked to the activation of pro-inflammatory bradykinin B2 receptors in non-neural cells [23, 24], suggesting that this class of calcium-permeable cation channels might be involved in both SOCE and ROCE signaling mechanisms downstream of the PLC pathway in neurons as well.
The present report focuses on the ill-defined role of TRPC channels in mammalian sensory pathways. Our data show that TRPC3, highly expressed in adult rodent DRG, is coupled to several classes of pro-inflammatory metabotropic receptors and plays a significant role in calcium homeostasis and sensitization in primary nociceptors, through its involvement in both SOCE and ROCE.
Results and discussion
Expression of the TRPC gene family in rat DRG
TRPC channels are involved in SOCE in DRG neurons
Contribution of TRPC3 to SOCE in DRG neurons
TRPC3 involvement in P2Y2 receptor transduction
Significant contribution of TRPC3 to PAR2-mediated calcium signaling
PAR2- and P2Y2-mediated sensitization of nociceptors is TRPC3-dependent
Taken together, these results strengthen the notion that TRPC3 channels are recruited in several pro-inflammatory metabotropic pathways, at least those triggered by the nucleotides ATP/UTP and trypsin-like proteases which are components of the “inflammatory soup”. TRPC3 channels also play a significant role in store- as well as receptor-operated calcium-dependent mechanisms in rat DRG neurons. The reported rise in basal intracellular calcium levels during inflammatory conditions is thought to mediate an increase in PKC activity, which has been shown to play a major role in neuronal sensitization [30, 31, 43]. TRPC3 contributes significantly to this process as shown by our in vitro sensitization data. Nevertheless, we cannot exclude a role of TRPC1 in the TRPC3-dependent ROCE and SOCE described here. Due to the documented heteromerization of store-linked TRPC1 with TRPC3 [17, 34, 35], it is likely that TRPC1 + 3 heteromers contribute to SOCE in DRG neurons as well. TRPC3 being a non-selective cation channel, its abnormal activation due to an upregulation of pro-inflammatory GPCRs such as P2Y2 and PAR2 could also mediate neuronal hyperexcitability through sustained depolarization. Although the conditional knockout of both TRPC3 and TRPC6 in Nav1.8+ DRG neurons did not induce behavioral deficits in acute pain responses , the mechanisms by which TRPC3 mediates calcium-dependent sensitization of nociceptors in inflammatory conditions will remain to be deciphered.
Our data provide evidence that the DAG-gated and PLC-linked TRPC3 channel is involved in Orai-independent SOCE in adult rat primary nociceptors in DRG, where it is the major TRPC subunit expressed along with TRPC1. We show that in these neurons TRPC3 is also functionally coupled to several inflammatory transductions triggering calcium-dependent pathways and peripheral sensitization, including UTP/P2Y2 and proteases/PAR2 signaling complexes. We propose that this unique dual contribution to SOCE and ROCE defines the calcium-permeable TRPC3 channel as a key regulator of calcium homeostasis in DRG neurons in normal or pathological pain conditions.
Tissue extraction for RNA isolation
All experimental procedures were approved by the McGill University Animal Care Committee and were in compliance with the guidelines of the Canadian Council on Animal Care. DRGs were collected from adult Sprague-Dawley rats (4-8 weeks, Charles River) and suspended in Dulbecco’s modified Eagles medium containing 10% heat inactivated fetal bovine serum (Invitrogen), 1% penicillin and streptomycin, and 1% L-glutamine. Following extraction, DRG neurons were dissociated with fire-polished glass pipettes and sieved on 40 μm filters, thus limiting primary cultures to small and medium diameter neurons. Dissociated neurons were plated on poly-D-lysine and laminin coated 60 mm tissue culture dishes, and left overnight at 37°C and 5% CO2 to recover. The following day, cells were collected with 1% trypsin-EDTA and centrifuged. The pellet was used to extract total RNA using Qiagen’s RNeasy Mini Kit as described by the manufacturer. To eliminate possible genomic DNA contamination, total RNA samples were treated with RNase-Free DNase (Qiagen) in accordance with the manufacturer’s protocol.
cDNA synthesis and RT-PCR
Total RNA DRG extracts were used as templates to synthesize single-strand cDNAs. Random hexamers (Invitrogen) and RNaseOUT Recombinant Ribonuclease Inhibitor (Invitrogen) were used with the Omniscript RT Kit (Qiagen) to reverse-transcribe the cDNA templates according to the manufacturer’s recommendations. cDNAs were used in subsequent PCR reactions to determine the expression of TRPC gene family members in adult rat DRGs.
In situ hybridization
Rat tissue was obtained from adult male Sprague-Dawley rats (n = 3). TRPC1 and TRPC3 mRNAs were detected by radioactive in situ hybridization (ISH), as previously described . Anti-sense 35S-radiolabeled riboprobes were directed to the 1616-2177, 2246-2706, 1269-1797, 1561-1976, 2129-2512, 1891-2207 and 1797-2560 sequences of the rat TRPC 1, 2, 3, 4, 5, 6, 7 mRNA, respectively. These riboprobes were designed to detect selectively each TRPC subunit transcript and sense probes were used as negative controls.
Primary cultures for calcium imaging and electrophysiology
DRG extraction (n = 30-40) was carried out on 1-2 month old Sprague-Dawley rats. Following extraction, DRG neurons were dissociated with fire-polished glass pipettes, filtered with 40 μm filters, and suspended in Dulbecco’s modified Eagles medium (DMEM) containing 10% heat inactivated fetal bovine serum (Invitrogen), 1% penicillin and streptomycin, and 1% L-glutamine. Nontransfected homogenized DRG neurons were plated on 35 mm glass bottom dishes coated with poly-D-lysine (Sigma-Aldrich) and laminin (BD Bioscience) at a density of 50-100,000 cells/dish, and incubated with 2 ml of complete DMEM media, at 37°C in 5% CO2 until recording and imaging.
For patch-clamp recording, DRG ganglia were mechanically triturated using fire-polished Pasteur pipettes as well, but after each trituration, partially dissociated cells were briefly centrifuged (1000 rpm), and the supernatant was collected. Dissociated cells were plated on 35-mm culture dishes (Starstedt; 2 ml/dish) coated previously with laminin and poly-D-lysine. Cells were incubated for 24 h to 48 h at 37°C in 5% CO2 before electrophysiological recording.
Overexpression and shRNA-mediated knockdown
Adult rat DRGs (n = 35-40) were transiently transfected using Amaxa Rat Neuron Nucleofector Kit (Lonza) and Nucleofector I (Amaxa), in accordance with the manufacturer’s guidelines. Nucleofected neurons were plated on 35 mm glass bottom dishes coated with poly-D-lysine and laminin for subsequent calcium imaging. Cultured neurons were maintained in Neurobasal-A medium (Invitrogen) supplemented with B-27 (Invitrogen), 1% penicillin and streptenomycin, and 1% L-glutamine, 17.5 μg/ml uridine (Sigma-Aldrich) and 7.5 μg/ml of 5-fluoro-2’-deoxyuridine (Sigma-Aldrich). Media was replaced every 48-72 hours and cultures were incubated at 37°C in 5% CO2.
Heterologous expression of TRPC3 was induced with co-nucleofection of 6 μg of mouse TRPC3 in pcDNA3 along with 2 μg of GFP plasmid. Recording experiments were carried out on transfected GFP+ DRG neurons 48-72 hours post-transfection. TRPC3-specific shRNA construct (Origene) was used to interfere with the translation of the endogenous TRPC3 subunits as previously described . Knockdown was performed by transient transfection of 6 μg GFP-tagged TRPC3 shRNA using Nucleofector I as described above. Cultures were incubated at 37°C in 5% CO2 for a period of 4-6 days for maximal knockdown before recording.
DRG neurons were plated on glass bottom dishes coated with poly-D-lysine- and laminin-coated dishes at a density of 50-100,000 cells/dish. Prior to recording, the cells were loaded with 5 μM Fura-2 AM (Molecular Probes) + 0.1% BSA for 40 min and then washed for 30 min with the extracellular solution (containing in mM: 152 NaCl, 5 KCl, 2 CaCl2, 1 MgCl2, 10 HEPES and 10 glucose, pH 7.4) at 37°C in 5% CO2. During recording, the cells were constantly perfused with the extracellular solution and stimulated with the appropriate agonist. Cells were selected using an inverted TE2000-U microscope (Nikon) equipped with 40X oil-immersion objective [CFI super(S) fluor, Nikon]. Fura-2 AM was excited at 340 nm and 380 nm every second and emission at 510 nm was detected by a high-resolution cooled CCD camera (Cool Snap-HQ, Roper Scientific/Photometrics) interfaced to a Pentium III PC. The variation in intracellular calcium levels was determined by the ratio of fluorescence at 340 nm and 380 nm (340/380 ratio) calculated using the Metafluor 7.0 software (Molecular Devices). For each cell, agonist-induced increase in intracellular calcium (Δ340/380) was determined by subtracting the baseline ratio from the peak ratio of the response, divided by the baseline. All experiments were conducted at room temperature. The SOCE and TRPC blocker SKF96365 (Tocris) was used. The compound Pyr10, a selective TRPC3 antagonist, was provided by Dr. Groschner (Institute of Biophysics, Medical University of Graz, Austria) . Store-operated calcium signaling was induced in cultured DRGs by applying the sarco/endoplasmic reticulum Ca2+ ATPase blocker thapsigargin (1 μM) for 7 minutes in calcium-free perfusion solution. Fluctuation of intracellular calcium levels was measured using single-cell microfluorescence. The P2Y2 agonist UTP (Tocris) and the small-molecule PAR2 agonist AC55541 (Tocris) were added to the calcium-free perfusion solution (100 μM for 7 min) to activate their respective Gq-coupled receptors in DRG neurons.
Whole-cell patch-clamp recordings on DRG neurons were conducted 24 hr post plating at room temperature. The internal solution of the pipette, pH 7.2, contained (in mM): 130 K-gluconate, 1 MgCl2, 10 HEPES, 5 EGTA, 3 MgATP, and 0.4 GTP. The bath solution, pH 7.4, contained (in mM): 152 NaCl, 5 KCl, 2 CaCl2, 1 MgCl2, 10 HEPES, and 10 glucose. Patch pipettes had a tip resistance of 3–8 MΩ. Electrophysiological recording experiments were performed using an Axopatch 200B amplifier and digitized with a Digidata 1322A interface (Molecular Devices). Traces were acquired and analyzed using pClamp 8.2 software (Molecular Devices). Recordings were low-pass filtered at 2 kHz and 5 kHz in voltage- and current-clamp configurations, respectively. Under current-clamp, action potentials were electrically-induced (50-200 pA) with 50 ms depolarizing pulses at fixed time intervals.
Student’s t tests were used for assessing statistical significance between two experimental conditions. Differences were considered significant at P < 0.05.
We are grateful to Dominique Blais (Montreal Neurological Institute) for her help with cell culture and transfection. This work was supported by grants from CIHR and AstraZeneca R&D Montreal.
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