- freely available
Pharmaceuticals 2010, 3(5), 1411-1425; doi:10.3390/ph3051411
Published: 11 May 2010
Abstract: Pathophysiological conditions such as inflammation, ischemia, infection and tissue injury can all evoke pain, and each is accompanied by local acidosis. Acid sensing ion channels (ASICs) are proton-gated cation channels expressed in both central and peripheral nervous systems. Increasing evidence suggests that ASICs represent essential sensors for tissue acidosis-related pain. This review provides an update on the role of ASICs in pain sensation and discusses their therapeutic potential for pain management.
Tissue acidosis occurs in various physiological and pathophysiological states, including inflammation, infection, ischemia, cancer, tissue injury and metabolic stress [1,2,3,4]. It has long been known that extracellular acidosis elicits pain [1,5]. The local drop in pH is first detected by primary sensory neurons. The molecular basis of proton-sensing has been actively studied since the proton-activated cation currents were observed in dorsal root ganglion (DRG) neurons almost two decades ago . Increasing evidence has identified two principal types of proton-gated channels: transient receptor potential vanilloid receptor-1 (TRPV1) and acid-sensing ion channels (ASICs) [7,8]. This review provides an update on the role of ASICs in pain sensation and discusses their therapeutic potential for pain management. The involvement in pain sensation of TRPV1 and other known acid-sensitive channels such as certain two-pore domain background K+ channels (TASK) and purinergic P2X receptors, will not be discussed within the scope of this review.
2. ASICs: An Overview
ASICs belong to the voltage-insensitive, amiloride-sensitive epithelial Na+ channel/degenerin (ENaC/DEG) family of cation channels [9,10]. They are widely expressed in both central and peripheral nervous systems. To date, at least four genes encoding six ASIC subunits have been cloned in mammals: ASIC1a, ASIC1b, ASIC2a, ASIC2b, ASIC3 and ASIC4 [10,11]. However, ASIC4 has not been shown to produce or modulate proton-evoked current and remains the least understood subunit [11,12].
The ASIC subunits share the same overall structure with other ENaC/DEG family members, which is characterized by two hydrophobic transmembrane domains, a large cysteine-rich extracellular loop and short intracellular N- and C-termini [10,13]. A recent study of the crystal structure of chicken ASIC1 indicates that three subunits are required to form a functional channel . It is proposed that the proton sensor of ASIC protein is distributed over multiple sites, particularly His-72 and Gly-430 in the extracellular loop [13,14,15,16]. How the protein binding at these distant sites is translated into channel gating is not yet fully understood .
Functional ASICs can be formed by homomultimers as well as heteromultimers [7,17]. Different homomeric and heteromeric ASIC channels have distinct kinetics, pH sensitivity, ion selectivity, tissue distribution and pharmacological properties [11,18,19,20]. The only known activator of ASICs is extracellular proton. When activated, ASICs are preferentially permeable to Na+, but the homomeric ASIC1a channels are also permeable to Ca2+ [11,21,22]. Four ASIC subunits (ASIC1a, ASIC1b, ASIC2a and ASIC3) can form functional homomultimers, whereas ASIC2b can not form functional channel by itself but may co-assemble with other ASIC subunits to form heteromultimers with new biophysical and pharmacological properties [20,23]. In heterologous cell systems, the pH of half-maximal activation (pH0.5) of homomeric ASIC channels differs: 6.2–6.8 for ASIC1a, 5.1–6.2 for ASIC1b, 4.1–5 for ASIC2a, and 6.2–6.7 for ASIC3 [16,17,21,24,25,26]. Most ASICs are therefore activated by changes in pH in the physiological and pathophysiological range. Both ASIC1a and ASIC1b homomeric channels generate a rapidly activating and inactivating current; ASIC2a activates and inactivates more slowly; and ASIC3 generates most rapidly activating and inactivating current but has biphasic inactivation kinetics with a sustained component [13,20]. In addition, it appears that the inactivating rate of ASIC1a, ASIC1b and ASIC2a increases with a decrease of stimulation pH (i.e. proton concentration increase), whereas the time constant of inactivation for ASIC3 remains constant despite changes in pH . The ASIC single channel conductance has been investigated for several homomeric and heteromeric ASIC channels and ranges from 10 to 15 pS .
Although the exact subunit composition (or subtypes) of ASICs in most neurons remains unclear, almost all ASIC subunits are known to be present in primary sensory neurons [17,18,19,27,28]. ASIC1a, ASIC1b, ASIC2b and ASIC3 are extensively expressed in small and medium nociceptive neurons [19,25,29,30]. ASIC2a and ASIC3 are also expressed in medium and large sensory neurons [19,31,32]. In the central nervous system, ASIC1a, ASIC2a and ASIC2b are widely expressed in the brain [24,33,34,35,36]. The presence of ASICs other than ASIC1a in the dorsal horn of spinal cord, where pain-related signals relay and transmitted to the brain, is less clear [37,38,39]. ASIC4, which cannot be activated by protons, has been detected in the pituitary gland, brain, spinal cord, and retina [16,40,41,42].
3. Role of ASICs in Pain Sensation
Physiological pain is initiated by high-threshold unmyelinated C or myelinated Aδ primary sensory neurons that feed into noceciptive pathways of the central nervous system [43,44]. The notion that ASICs function as a major sensor of acid-evoked pain is supported by the following evidence: ASICs are expressed in peripheral sensory neurons as well as spinal nociceptive pathways (e.g., spinal cord dorsal horn); different homomeric and heteromeric ASICs are well positioned to detect and differentiate pH variations in both physiological and pathophysiological ranges; and more importantly, inhibiting ASICs has been shown to relieve pain in a variety of pain syndromes in both animals and humans ([11,23,45], Figure 1).
3.1. Primary inflammatory pain
Direct perfusion of acidic solutions or iontophoresis of protons into the skin causes pain in humans [46,47,48]. This acid-evoked pain can be significantly reduced by amiloride (, Figure 1A), a common inhibitor of ASICs, and nonsteroid anti-inflammatory drugs (NSAIDs) such as declofenac and ibuprofen, which selectively inhibit ASIC1a and ASIC3, respectively . Previous study shows that the human subject feels pain even at pH 7.0, which is low enough for the activation of ASIC1a and ASIC3 . A recent study in rats further suggests that peripheral ASIC3 channels are the essential sensors of cutaneous acidic pain in both normal and inflammatory conditions . The hypothesis was based upon these observations: first, rat cutaneous sensory neurons display a high level of ASIC3 channels, which, when activated by slight acidification (pH 7.0), depolarize the neurons and trigger action potentials; second, very moderate acidifications induce a significant increase in skin C-fibers firing, which is totally inhibited by APETx2, a specific ASIC3 inhibitor; third, primary inflammatory-induced hyperalgesia is significantly inhibited by APETx2 and also by the in vivo knockdown of ASIC3 with a specific siRNA, whereas PcTx1, a specific blocker of homomeric ASIC1a channels , has no significantly effect (Figure 1B).
Indeed, inflammation is known to induce a marked increase of the ASIC channel expression in primary sensory neurons; for example, the mRNA level of ASIC3 is increased by up to 15 fold in complete Freund’s adjuvant (CFA) -induced inflammation . The increase in ASICs expression is largely abolished by NSAIDs in these neurons . In addition, in isolated DRG neurons, a mixture of the proinflammatory mediators, including nerve growth factor, serotonin, interleukin-1 and bradykinin, increases the number of ASIC expressing neurons as well as the ASIC-like current density in these sensory neurons .
The involvement of ASICs in muscle and joint pain associated with inflammation has also been studied [53,54,55,56,57]. Intramuscular injection of carrageenan has been widely used to induce an animal model of chronic inflammatory muscle pain due to the local inflammation and hyperalgesia at the injection site that lasts for weeks, and can spread to the contralateral side when the inflammation becomes chronic . A recent study demonstrates that, 24 hours after carrageenan-induced muscle inflammation in mice, the mRNA levels of ASIC2 and ASIC3 (but not ASIC1) in lumbar DRG neurons increase bilaterally . The study also shows that both the primary and secondary hyperalgesia (increased response to noxious stimuli at and outside the site of injury, respectively) can be reversed by nonselective ASIC inhibitor A-317567. In a carrageenan-induced mouse arthritis model, the knee joint afferents with ASIC3 immunoreactivity increase from 31% to 50% after the induced joint inflammation, indicating that ASIC3 plays an important role in inflammatory joint pain .
The role of ASICs in primary inflammatory pain has been investigated recently in gene-targeted mice, and the data are not conclusive. In several studies mentioned above [53,54,57,59], the use of ASIC knockout mice seems to provide a clear case that ASICs, especially ASIC3, play a major role in primary inflammatory pain. However, other studies have shown that disruption of ASICs may increase the sensitivity to painful stimuli instead [60,61,62]. The reasons for these discrepancies are not known, but may be due to the variability in genetic background or species, differences in inflammatory models and research methodologies employed, complementary effect after genetic disruption, etc. [11,23,39,63].
3.2. Cardiac pain
Pain is the only sensation that can be evoked from most internal organs. Visceral pain can be considered as part of the defense reactions of the body against harmful stimuli, particularly of those that impinge on the mucosal lining of hollow organs . It has considerable clinical relevance, and the underlying neurobiological mechanisms differ from those of somatic nociceptive or neuropathic pain .
Myocardial ischemia can lead to pain or discomfort within the chest, termed angina pectoris . It is generally believed that such pain results from the activation of cardiac sensory neurons by a number of chemical mediators released during tissue ischemia, including lactic acid . ASIC3 has been considered a major sensor for lactic acidosis created by anaerobic metabolism because it is expressed at extremely high levels in sensory neurons that innervate the heart [26,66,67]. It has been shown that both rat ASIC3 homomultimers and ASIC2a/3 heteromultimers produce sustained inward currents in response to the modest pH changes (7.3-6.7) typical of muscle ischemia; the sustained current is caused by a range of pH where there is an overlap between inactivation and activation of the ASIC channel . Lactate can significantly enhance proton-evoked gating, probably mediated through a mechanism involving calcium chelation [68,69]. Studies in ASIC knockout mice further show that the acid-evoked currents from ASIC3-/- cardiac afferents match the properties of ASIC2a channels, and currents from ASIC2-/- cardiac afferents match the properties of ASIC3 channels . These results seem to suggest that ASIC2a and ASIC3 are indeed the major ASIC subunits serving as the acid sensor in cardiac sensory neurons.
3.3. GI pain and respiratory sensation
Luminal acidity is a physiological challenge in the foregut, and acidosis may occur throughout the gastrointestinal (GI) tract as a result of inflammation, ischemia, cancer, microbial activity, or over distension of GI wall . Acid is known to contribute to the pain associated with GI diseases such as dyspepsia, peptic ulcer, and gastro-esophageal reflux disease. ASIC1, ASIC2 and ASIC3 are all expressed in GI sensory neurons, and ASIC3 appears to be the most abundant . Retrograde tracing shows that 75% of the nodose ganglion neurons and 82% of the DRG neurons projecting to the rat stomach express ASIC3 . Quantitative RT-PCR of laser captured colonic neurons and fluorescence in situ hybridization experiments reveal that ASIC3 is the most abundant ASIC transcript within thoracolumbar DRG, followed by ASIC2 and ASIC1 . In addition, the expression of ASIC3, but not ASIC1 and ASIC2, is upregulated in the colonic mucosa of patients with inflammatory bowel disease . The importance of ASIC3 in modulating GI nociception is demonstrated further by studies using ASIC knockout mice. ASIC3−/− mice were reported to have markedly reduced visceral mechanosensitivity when compared to control animals and ASIC1−/− or ASIC2−/− mice . Another recent study shows that gastric acid hyperresponsiveness is absent in ASIC3−/− mice but was fully preserved in ASIC2−/− mice . Interestingly, the non-selective ASIC channel blocker benzamil only partially attenuates mechanosensitivity in gastroesophageal afferents, whereas it markedly attenuates mechanosensitivity in colonic afferents . The differential role of ASIC3 in the upper and lower GI tract indicates that this channel may serve as a key target for modulating GI nociception .
Most sensory inputs arising from airways and lung structures are conducted in vagus nerves and their branches, and the majority of vagal bronchopulmonary sensory nerves are nociceptive C-fibers [77,78]. Activation of bronchopulmonary C-fibers elicits irritation, cough, bronchoconstriction, burning, choking and breathless sensations [79,80]. In contrast to other visceral organs (e.g., heart, GI tract, etc.), pain sensation is generally not detected in the lower respiratory tract and lung parenchyma. Endogenous airway acidification has been documented in various airway inflammatory diseases including asthma and chronic obstructive pulmonary disease [2,81,82]. Airway exposure to endogenous or exogenous acid (e.g., gastroesophageal reflux with microaspiration, air pollution-induced acid fogs, etc.) is known to evoke cardiorespiratory symptoms such as cough, bronchospasm and dyspnea that are at least partially mediated through the activation of bronchopulmonary C-fibers and the subsequent reflex responses [82,83,84]. Recent studies have shown that physiological- and pathophysiological-relevant acidification indeed activates vagal bronchopulmonary C-fibers, which is likely mediated through the activation of both ASICs and TRPV1 [84,85]. By using retrograde labeling and multi-cell RT-PCR, a recent study shows that the mRNA of all four functional ASIC subunits (1a, 1b, 2a, and 3) are expressed in pulmonary sensory neurons . Patch clamp studies show that the native ASICs expressed in these neurons are likely heteromultimers although the specific ASIC subunit combinations are not yet known [85,86].
3.4. Chronic pathological pain
Chronic pain generally falls into two categories: inflammatory and neuropathic pain [39,87]. The former is initiated by inflammation associated with tissue damage; whereas the latter is defined as “pain arising as a direct consequence of a lesion or disease affecting the somatosensory system”, and can be caused by a number of different diseases (e.g., diabetes, stroke, tumor growth, HIV infection), medical interventions (e.g., chemotherapy, surgery), and injuries (e.g., brachial plexus avulsion) [88,89,90]. It is generally believed that the exaggerated nociceptive sensation can originate from either increased sensitivity of peripheral nociceptors (peripheral sensitization), increased excitability of spinal cord dorsal horn neurons (central sensitization), or alternations in descending control from the brain [39,91,92]. Although the clinical features of inflammatory and neuropathic pain differ substantially, previous studies indicate that the local inflammation of peripheral nerves may play an important role in the generation of neuropathic pain [93,94]. In addition, these two types of chronic pain share many common central spinal and brain mechanisms .
ASICs play an essential role in pain sensation not only from the standpoint of their peripheral nociceptive function, but also their involvement in the development of central sensitization and pain hypersensitivity . Spinal dorsal horn neurons express a high density of homomeric ASIC1a channels, and the expression of these channels is upregulated by peripheral inflammation [37,38]. Blocking of ASIC1a by spinal infusion of its specific inhibitor PcTx1 or suppression of ASIC1a expression using specific antisense oligonucleotides markedly attenuated CFA-induced thermal and mechanical hypersensitivity (, Figure 1C). In animal models of neuropathic pain, ASIC3 immunoreactivity in rat DRG neurons is elevated following lumbar disc herniation , and intrathecal injection of PcTx1 reverses the thermal and mechanical nociception in rats with chronic constriction injury of sciatic nerve . In addition, recent studies indicate that ASIC1a may play a key role in neuronal injury after ischemic stroke [97,98,99].
4. ASICs as a Potential Therapeutic Target for Pain Treatment
Although extracellular proton is the only known activator of ASICs, increasing evidence shows that the proton-gating of ASICs can be modulated by a variety of factors. As we described earlier, the expression of ASICs is upregulated following inflammation and tissue injury [37,38,49,95]. Many proinflammatory mediators such as nerve growth factor, serotonin, interleukin-1 and bradykinin increase ASIC expression and acid-evoked ASIC currents . The activity of ASICs, especially ASIC1a and ASIC3-containing channels, are upregulated by FMRF-amide and chronic inflammation related FMRF-amide like peptides including neuropeptide FF and neuropeptide AF [100,101,102,103,104,105]. ASICs are also modulated by a number of factors that are generated or released during ischemia, inflammation and acidosis, such as lactate [68,106], proteases [86,107,108], redox reagents [109,110], nitric oxide  and arachidonic acid [106,112]. In addition, many cations (such as Zn2+ and Ca2+) and protein kinases (such as PKA and PKC) can modulate certain subunit-containing ASIC channels . Although the mechanisms underlying the regulatory effect of most of the ASIC modulators are not fully understood, many of them (such as lactate, proteases, nitric oxide and redox reagents) are believed to modulate the proton-dependent channel activity through an interaction with the large extracellular loop of ASIC subunits [68,107,109,111,112]. When tested in native sensory neurons or in heterogous expression systems, most ASIC subtypes are known to generate transient inward currents then desensitize rapidly [13,20]. The property of ASICs to be modulated by this large variety of endogenous chemical substances probably allows them to detect and respond to the sustained acidosis that occurs during inflammatory and many other pathological conditions [11,113]. Therefore, delineating the mechanisms underling the modulation of ASICs by these molecules might be critical for understanding the physiological and pathological roles of these channels and for establishing future targets for pharmacological intervention .
ASICs emerged as a potential therapeutic target for pain treatment when amiloride, a non-selective ASIC blocker, was shown to attenuate the intradermal acid infusion-evoked pain in humans [47,48]. Local injection of amiloride or its derivative benzamil significantly reduces nociceptive behaviors induced by serotonin, capsaicin or formalin under acidic conditions . NSAIDs, which are known for their ability to inhibit prostaglandin synthesis and also their direct inhibition of ASICs, abolish the inflammation-induced increase in ASICs expression [49,115] and significantly reduce the acid-evoked pain . Another nonselective ASIC inhibitor A-317567 can reverse both the primary and secondary hyperalgesia, and appear to be more potent than amiloride in both in vitro and in vivo preparations . To date, two subunit-selective ASIC inhibitors have been identified. PcTx1, a short peptide isolated from the venom of the South American tarantula Psalmopoeus cambridgei, potently and specifically inhibits ASIC1a homomultimers, while does not affect ASIC1a-containing heteromultimers [51,116]. APETx2 from the sea anemone Anthopleura elegantissima is another ASIC blocker that selectively and effectively inhibits homo- and hetero-meric ASIC3 channels [16,117]. Given that different ASIC subtypes seem to have distinct property, tissue distribution and contribution to pain sensation, specific ASIC inhibitors can be useful as a pharmacological tool in pain research as well as a novel avenue in pain therapy .
Tissue acidosis occurs in various physiological and pathophysiological states such as inflammation, ischemia, or tissue injury. The local drop in pH is detected by primary sensory neurons, the signals of which feed into nociceptive pathways of central nervous system and produces pain sensation. Studies using ASIC-gene-targeted approaches and ASICs inhibitors in various pain models indicate that ASICs function as the essential sensors of acid-evoked pain and appear as a potential therapeutic target for pain therapy. However, a better understanding of the structure, activation and modulation mechanisms, and development of additional potent and specific ASIC inhibitors suitable for clinical use will be needed for alleviating acid-related pain syndromes.
The work in author’s laboratory was supported by National Institute of Health (R03AI076714 to Q Gu, and R01HL096914 and R01HL058686 to L-Y Lee) and American Heart Association (0835320N to Q. Gu).
- Reeh, P.W.; Steen, K.H. Tissue acidosis in nociception and pain. Prog. Brain Res. 1996, 113, 143–151. [Google Scholar]
- Hunt, J.F.; Fang, K.; Malik, R.; Snyder, A.; Malhotra, N.; Platts-Mills, T.A.; Gaston, B. Endogenous airway acidification: Implications for asthma pathophysiology. Am. J. Respir. Crit. Care Med. 2000, 161, 694–699. [Google Scholar]
- Benson, C.J.; Sutherland, S.P. Toward an understanding of the molecules that sense myocardial ischemia. Ann. N. Y. Acad. Sci. 2001, 940, 96–109. [Google Scholar]
- Mantyh, P.W.; Clohisy, D.R.; Koltzenburg, M.; Hunt, S.P. Molecular mechanisms of cancer pain. Nat. Rev. Cancer 2002, 2, 201–209. [Google Scholar]
- Steen, K.H.; Reeh, P.W. Sustained graded pain and hyperalgesia from harmless experimental tissue acidosis in human skin. Neurosci. Lett. 1993, 154, 113–116. [Google Scholar]
- Bevan, S.; Yeats, J. Protons activate a cation conductance in a sub-population of rat dorsal root ganglion neurones. J. Physiol. 1991, 433, 145–161. [Google Scholar]
- Waldmann, R.; Lazdunski, M. H(+)-gated cation channels: neuronal acid sensors in the NaC/DEG family of ion channels. Curr. Opin. Neurobiol. 1998, 8, 418–424. [Google Scholar]
- Caterina, M.J.; Julius, D. The vanilloid receptor: a molecular gateway to the pain pathway. Annu. Rev. Neurosci. 2001, 24, 487–517. [Google Scholar]
- Kellenberger, S.; Schild, L. Epithelial sodium channel/degenerin family of ion channels: A variety of functions for a shared structure. Physiol. Rev. 2002, 82, 735–767. [Google Scholar]
- Krishtal, O. The ASICs: signaling molecules? Modulators? Trends Neurosci. 2003, 26, 477–483. [Google Scholar] [CrossRef] [PubMed]
- Wemmie, J.A.; Price, M.P.; Welsh, M.J. Acid-sensing ion channels: Advances, questions and therapeutic opportunities. Trends Neurosci. 2006, 29, 578–586. [Google Scholar]
- Akopian, A.N.; Chen, C.C.; Ding, Y.; Cesare, P.; Wood, J.N. A new member of the acid-sensing ion channel family. Neuroreport 2000, 11, 2217–2222. [Google Scholar]
- Holzer, P. Acid-sensitive ion channels and receptors. Handb. Exp. Pharmacol. 2009, 194, 283–332. [Google Scholar]
- Jasti, J.; Furukawa, H.; Gonzales, E.B.; Gouaux, E. Structure of acid-sensing ion channel 1 at 1.9 Ǻ resolution and low pH. Nature 2007, 449, 316–323. [Google Scholar] [PubMed]
- Waldmann, R. Proton-gated cation channels—Neuronal acid sensors in the central and peripheral nervous system. Adv. Exp. Med. Biol. 2001, 502, 293–304. [Google Scholar]
- Diochot, S.; Salinas, M.; Baron, A.; Escoubas, P.; Lazdunski, M. Peptides inhibitors of acid-sensing ion channels. Toxicon 2007, 49, 271–284. [Google Scholar]
- Benson, C.J.; Xie, J.; Wemmie, J.A.; Price, M.P.; Henss, J.M.; Welsh, M.J.; Snyder, P.M. Heteromultimers of DEG/ENaC subunits form H+-gated channels in mouse sensory neurons. Proc. Natl. Acad. Sci. USA 2002, 99, 2338–2343. [Google Scholar]
- Waldmann, R.; Champigny, G.; Lingueglia, E.; De Weille, J.R.; Heurteaux, C.; Lazdunski, M. H(+)-gated cation channels. Ann. N. Y. Acad. Sci. 1999, 868, 67–76. [Google Scholar]
- Alvarez de la Rosa, D.; Zhang, P.; Shao, D.; White, F.; Canessa, C.M. Functional implications of the localization and activity of acid-sensitive channels in rat peripheral nervous system. Proc. Natl. Acad. Sci. USA. 2002, 99, 2326–2331. [Google Scholar]
- Hesselager, M.; Timmermann, D.B.; Ahring, P.K. pH dependency and desensitization kinetics of heterologously expressed combinations of acid-sensing ion channel subunits. J. Biol. Chem. 2004, 279, 11006–11015. [Google Scholar]
- Waldmann, R.; Champigny, G.; Bassilana, F.; Heurteaux, C.; Lazdunski, M. A proton-gated cation channel involved in acid-sensing. Nature 1997, 386, 173–177. [Google Scholar]
- Yermolaieva, O.; Leonard, A.S.; Schnizler, M.K.; Abboud, F.M.; Welsh, M.J. Extracellular acidosis increases neuronal cell calcium by activating acid-sensing ion channel 1a. Proc. Natl. Acad. Sci. USA 2004, 101, 6752–6757. [Google Scholar]
- Dubé, G.R.; Elagoz, A.; Mangat, H. Acid sensing ion channels and acid nociception. Curr. Pharm. Des. 2009, 15, 1750–1766. [Google Scholar]
- Price, M.P.; Snyder, P.M.; Welsh, M.J. Cloning and expression of a novel human brain Na+ channel. J. Biol. Chem. 1996, 271, 7879–7882. [Google Scholar]
- Chen, C.C.; England, S.; Akopian, A.N.; Wood, J.N. A sensory neuron-specific, proton-gated ion channel. Proc. Natl. Acad. Sci. USA. 1998, 95, 10240–10245. [Google Scholar]
- Sutherland, S.P.; Benson, C.J.; Adelman, J.P.; McCleskey, E.W. Acid-sensing ion channel 3 matches the acid-gated current in cardiac ischemia-sensing neurons. Proc. Natl. Acad. Sci. USA. 2001, 98, 711–716. [Google Scholar]
- Page, A.J.; Brierley, S.M.; Martin, C.M.; Price, M.P.; Symonds, E.; Butler, R.; Wemmie, J.A.; Blackshaw, L.A. Different contributions of ASIC channels 1a, 2, and 3 in gastrointestinal mechanosensory function. Gut 2005, 54, 1408–1415. [Google Scholar] [CrossRef] [PubMed]
- Hughes, P.A.; Brierley, S.M.; Young, R.L.; Blackshaw, L.A. Localization and comparative analysis of acid-sensing ion channel (ASIC1, 2, and 3) mRNA expression in mouse colonic sensory neurons within thoracolumbar dorsal root ganglia. J. Comp. Neurol. 2007, 500, 863–875. [Google Scholar] [CrossRef] [PubMed]
- Olson, T.H.; Riedl, M.S.; Vulchanova, L.; Ortiz-Gonzalez, X.R.; Elde, R. An acid sensing ion channel (ASIC) localizes to small primary afferent neurons in rats. Neuroreport 1998, 9, 1109–1113. [Google Scholar]
- Ugawa, S.; Ueda, T.; Yamamura, H.; Shimada, S. In situ hybridization evidence for the coexistence of ASIC and TRPV1 within rat single sensory neurons. Brain Res. Mol. Brain Res. 2005, 136, 125–133. [Google Scholar] [PubMed]
- Price, M.P.; McIlwrath, S.L.; Xie, J.; Cheng, C.; Qiao, J.; Tarr, D.E.; Sluka, K.A.; Brennan, T.J.; Lewin, G.R.; Welsh, M.J. The DRASIC cation channel contributes to the detection of cutaneous touch and acid stimuli in mice. Neuron 2001, 32, 1071–1083. [Google Scholar] [CrossRef] [PubMed]
- Xie, J.; Price, M.P.; Berger, A.L.; Welsh, M.J. DRASIC contributes to pH-gated currents in large dorsal root ganglion sensory neurons by forming heteromultimeric channels. J. Neurophysiol. 2002, 87, 2835–2843. [Google Scholar]
- Wemmie, J.A.; Chen, J.; Askwith, C.C.; Hruska-Hageman, A.M.; Price, M.P.; Nolan, B.C.; Yoder, P.G.; Lamani, E.; Hoshi, T.; Freeman, J.H., Jr.; Welsh, M.J. The acid-activated ion channel ASIC contributes to synaptic plasticity, learning, and memory. Neuron 2002, 34, 463–477. [Google Scholar] [CrossRef] [PubMed]
- Alvarez de la Rosa, D.; Krueger, S.R.; Kolar, A.; Shao, D.; Fitzsimonds, R.M.; Canessa, C.M. Distribution, subcellular localization and ontogeny of ASIC1 in the mammalian central nervous system. J. Physiol. 2003, 546, 77–87. [Google Scholar]
- Jovov, B.; Tousson, A.; McMahon, L.L.; Benos, D.J. Immunolocalization of the acid-sensing ion channel 2a in the rat cerebellum. Histochem. Cell Biol. 2003, 119, 437–446. [Google Scholar]
- Askwith, C.C.; Wemmie, J.A.; Price, M.P.; Rokhlina, T.; Welsh, M.J. Acid-sensing ion channel 2 (ASIC2) modulates ASIC1 H+-activated currents in hippocampal neurons. J. Biol. Chem. 2004, 279, 18296–18305. [Google Scholar]
- Wu, L.J.; Duan, B.; Mei, Y.D.; Gao, J.; Chen, J.G.; Zhuo, M.; Xu, L.; Wu, M.; Xu, T.L. Characterization of acid-sensing ion channels in dorsal horn neurons of rat spinal cord. J. Biol. Chem. 2004, 279, 43716–43724. [Google Scholar]
- Duan, B.; Wu, L.J.; Yu, Y.Q.; Ding, Y.; Jing, L.; Xu, L.; Chen, J.; Xu, T.L. Upregulation of acid-sensing ion channel ASIC1a in spinal dorsal horn neurons contributes to inflammatory pain hypersensitivity. J. Neurosci. 2007, 27, 11139–11148. [Google Scholar]
- Xu, T.L.; Duan, B. Calcium-permeable acid-sensing ion channel in nociceptive plasticity: A new target for pain control. Prog. Neurobiol. 2009, 87, 171–180. [Google Scholar]
- Gründer, S.; Geissler, H.S.; Bässler, E.L.; Ruppersberg, J.P. New member of acid-sensing ion channels from pituitary gland. Neuroreport 2000, 11, 1607–1611. [Google Scholar]
- Brockway, L.M.; Zhou, Z.H.; Bubien, J.K.; Jovov, B.; Benos, D.J.; Keyser, K.T. Rabbit retinal neurons and glia express a variety of ENaC/DEG subunits. Am. J. Physiol. Cell Physiol. 2002, 283, C126–C134. [Google Scholar]
- Lingueglia, E. Acid-sensing ion channels in sensory perception. J. Biol. Chem. 2007, 282, 17325–17329. [Google Scholar]
- Basbaum, A.I.; Bautista, D.M.; Scherrer, G.; Julius, D. Cellular and molecular mechanisms of pain. Cell 2009, 139, 267–284. [Google Scholar]
- Costigan, M.; Scholz, J.; Woolf, C.J. Neuropathic pain: a maladaptive response of the nervous system to damage. Annu. Rev. Neurosci. 2009, 32, 1–32. [Google Scholar]
- McCleskey, E.W.; Gold, M.S. Ion channels of nociception. Annu. Rev. Physiol. 1999, 61, 835–856. [Google Scholar]
- Steen, K.H.; Issberner, U.; Reeh, P.W. Pain due to experimental acidosis in human skin: Evidence for non-adapting nociceptor excitation. Neurosci. Lett. 1995, 199, 29–32. [Google Scholar]
- Ugawa, S.; Ueda, T.; Ishida, Y.; Nishigaki, M.; Shibata, Y.; Shimada, S. Amiloride-blockable acid-sensing ion channels are leading acid sensors expressed in human nociceptors. J. Clin. Invest. 2002, 110, 1185–1190. [Google Scholar]
- Jones, N.G.; Slater, R.; Cadiou, H.; McNaughton, P.; McMahon, S.B. Acid-induced pain and its modulation in humans. J. Neurosci. 2004, 24, 10974–10979. [Google Scholar]
- Voilley, N.; de Weille, J.; Mamet, J.; Lazdunski, M. Nonsteroid anti-inflammatory drugs inhibit both the activity and the inflammation-induced expression of acid-sensing ion channels in nociceptors. J. Neurosci. 2001, 21, 8026–8033. [Google Scholar]
- Deval, E.; Noël, J.; Lay, N.; Alloui, A.; Diochot, S.; Friend, V.; Jodar, M.; Lazdunski, M.; Lingueglia, E. ASIC3, a sensor of acidic and primary inflammatory pain. EMBO J. 2008, 27, 3047–3055. [Google Scholar]
- Escoubas, P.; De Weille, J.R.; Lecoq, A.; Diochot, S.; Waldmann, R.; Champigny, G.; Moinier, D.; Ménez, A.; Lazdunski, M. Isolation of a tarantula toxin specific for a class of proton-gated Na+ channels. J. Biol. Chem. 2000, 275, 25116–25121. [Google Scholar]
- Mamet, J.; Baron, A.; Lazdunski, M.; Voilley, N. Proinflammatory mediators, stimulators of sensory neuron excitability via the expression of acid-sensing ion channels. J. Neurosci. 2002, 22, 10662–10670. [Google Scholar]
- Sluka, K.A.; Price, M.P.; Breese, N.M.; Stucky, C.L.; Wemmie, J.A.; Welsh, M.J. Chronic hyperalgesia induced by repeated acid injections in muscle is abolished by the loss of ASIC3, but not ASIC1. Pain 2003, 106, 229–239. [Google Scholar]
- Sluka, K.A.; Radhakrishnan, R.; Benson, C.J.; Eshcol, J.O.; Price, M.P.; Babinski, K.; Audette, K.M.; Yeomans, D.C.; Wilson, S.P. ASIC3 in muscle mediates mechanical, but not heat, hyperalgesia associated with muscle inflammation. Pain 2007, 129, 102–112. [Google Scholar] [CrossRef] [PubMed]
- Fujii, Y.; Ozaki, N.; Taguchi, T.; Mizumura, K.; Furukawa, K.; Sugiura, Y. TRP channels and ASICs mediate mechanical hyperalgesia in models of inflammatory muscle pain and delayed onset muscle soreness. Pain 2008, 140, 292–304. [Google Scholar]
- Ikeuchi, M.; Kolker, S.J.; Burnes, L.A.; Walder, R.Y.; Sluka, K.A. Role of ASIC3 in the primary and secondary hyperalgesia produced by joint inflammation in mice. Pain 2008, 137, 662–669. [Google Scholar]
- Walder, R.Y.; Rasmussen, L.A.; Rainier, J.D.; Light, A.R.; Wemmie, J.A.; Sluka, K.A. ASIC1 and ASIC3 play different roles in the development of Hyperalgesia after inflammatory muscle injury. J. Pain 2010, 11, 210–218. [Google Scholar]
- Radhakrishnan, R.; Moore, S.A.; Sluka, K.A. Unilateral carrageenan injection into muscle or joint induces chronic bilateral hyperalgesia in rats. Pain 2003, 104, 567–577. [Google Scholar]
- Ikeuchi, M.; Kolker, S.J.; Sluka, K.A. Acid-sensing ion channel 3 expression in mouse knee joint afferents and effects of carrageenan-induced arthritis. J. Pain 2009, 10, 336–342. [Google Scholar]
- Drew, L.J.; Rohrer, D.K.; Price, M.P.; Blaver, K.E.; Cockayne, D.A.; Cesare, P.; Wood, J.N. Acid-sensing ion channels ASIC2 and ASIC3 do not contribute to mechanically activated currents in mammalian sensory neurones. J. Physiol. 2004, 556, 691–710. [Google Scholar]
- Mogil, J.S.; Breese, N.M.; Witty, M.F.; Ritchie, J.; Rainville, M.L.; Ase, A.; Abbadi, N.; Stucky, C.L.; Seguela, P. Transgenic expression of a dominant-negative ASIC3 subunit leads to increased sensitivity to mechanical and inflammatory stimuli. J. Neurosci. 2005, 25, 9893–9901. [Google Scholar]
- Staniland, A.A.; McMahon, S.B. Mice lacking acid-sensing ion channels (ASIC) 1 or 2, but not ASIC3, show increased pain behaviour in the formalin test. Eur. J. Pain 2009, 13, 554–563. [Google Scholar] [CrossRef] [PubMed]
- Sluka, K.A.; Winter, O.C.; Wemmie, J.A. Acid-sensing ion channels: A new target for pain and CNS diseases. Curr. Opin. Drug Discov. Devel. 2009, 12, 693–704. [Google Scholar]
- Cervero, F.; Laird, J.M. Understanding the signaling and transmission of visceral nociceptive events. J. Neurobiol. 2004, 61, 45–54. [Google Scholar]
- Yagi, J.; Wenk, H.N.; Naves, L.A.; McCleskey, E.W. Sustained currents through ASIC3 ion channels at the modest pH changes that occur during myocardial ischemia. Circ. Res. 2006, 99, 501–509. [Google Scholar]
- Benson, C.J.; Eckert, S.P.; McCleskey, E.W. Acid-evoked currents in cardiac sensory neurons: A possible mediator of myocardial ischemic sensation. Circ. Res. 1999, 84, 921–928. [Google Scholar]
- Naves, L.A.; McCleskey, E.W. An acid-sensing ion channel that detects ischemic pain. Braz. J. Med. Biol. Res. 2005, 38, 1561–1569. [Google Scholar]
- Immke, D.C.; McCleskey, E.W. Lactate enhances the acid-sensing Na+ channel on ischemia-sensing neurons. Nat. Neurosci. 2001, 4, 869–870. [Google Scholar]
- Immke, D.C.; McCleskey, E.W. Protons open acid-sensing ion channels by catalyzing relief of Ca2+ blockade. Neuron 2003, 37, 75–84. [Google Scholar]
- Hattori, T.; Chen, J.; Harding, A.M.; Price, M.P.; Lu, Y.; Abboud, F.M.; Benson, C.J. ASIC2a and ASIC3 heteromultimerize to form pH-sensitive channels in mouse cardiac dorsal root ganglia neurons. Circ. Res. 2009, 105, 279–286. [Google Scholar]
- Holzer, P. Taste receptors in the gastrointestinal tract. V. Acid sensing in the gastrointestinal tract. Am. J. Physiol. Gastrointest. Liver Physiol. 2007, 292, G699–G705. [Google Scholar] [CrossRef]
- Schicho, R.; Florian, W.; Liebmann, I.; Holzer, P.; Lippe, I.T. Increased expression of TRPV1 receptor in dorsal root ganglia by acid insult of the rat gastric mucosa. Eur. J. Neurosci. 2004, 19, 1811–1818. [Google Scholar]
- Yiangou, Y.; Facer, P.; Smith, J.A.; Sangameswaran, L.; Eglen, R.; Birch, R.; Knowles, C.; Williams, N.; Anand, P. Increased acid-sensing ion channel ASIC-3 in inflamed human intestine. Eur. J. Gastroenterol. Hepatol. 2001, 13, 891–896. [Google Scholar]
- Wultsch, T.; Painsipp, E.; Shahbazian, A.; Mitrovic, M.; Edelsbrunner, M.; Lazdunski, M.; Waldmann, R.; Holzer, P. Deletion of the acid-sensing ion channel ASIC3 prevents gastritis-induced acid hyperresponsiveness of the stomach-brainstem axis. Pain 2008, 134, 245–253. [Google Scholar]
- Page, A.J.; Brierley, S.M.; Martin, C.M.; Hughes, P.A.; Blackshaw, L.A. Acid sensing ion channels 2 and 3 are required for inhibition of visceral nociceptors by benzamil. Pain 2007, 133, 150–160. [Google Scholar]
- Hobson, A.R.; Aziz, Q. Modulation of visceral nociceptive pathways. Curr. Opin. Pharmacol. 2007, 7, 593–597. [Google Scholar]
- Coleridge, H.M.; Coleridge, J.C. Pulmonary reflexes: neural mechanisms of pulmonary defense. Annu. Rev. Physiol. 1994, 56, 69–91. [Google Scholar]
- Lee, L.Y.; Pisarri, T.E. Afferent properties and reflex functions of bronchopulmonary C-fibers. Respir. Physiol. 2001, 125, 47–65. [Google Scholar]
- Fisher, J.T. The TRPV1 ion channel: implications for respiratory sensation and dyspnea. Respir. Physiol. Neurobiol. 2009, 167, 45–52. [Google Scholar]
- Lee, L.Y. Respiratory sensations evoked by activation of bronchopulmonary C-fibers. Respir. Physiol. Neurobiol. 2009, 167, 26–35. [Google Scholar]
- Ricciardolo, F.L.; Steinhoff, M.; Amadesi, S.; Guerrini, R.; Tognetto, M.; Trevisani, M.; Creminon, C.; Bertrand, C.; Bunnett, N.W.; Fabbri, L.M.; Salvadori, S.; Geppetti, P. Presence and bronchomotor activity of protease-activated receptor-2 in guinea pig airways. Am. J. Respir. Crit. Care Med. 2000, 161, 1672–1680. [Google Scholar] [PubMed]
- Kodric, M.; Shah, A.N.; Fabbri, L.M.; Confalonieri, M. An investigation of airway acidification in asthma using induced sputum: A study of feasibility and correlation. Am. J. Respir. Crit. Care Med. 2007, 175, 905–910. [Google Scholar]
- Ricciardolo, F.L.; Gaston, B.; Hunt, J. Acid stress in the pathology of asthma. J. Allergy Clin. Immunol. 2004, 113, 610–619. [Google Scholar]
- Kollarik, M.; Ru, F.; Undem, B.J. Acid-sensitive vagal sensory pathways and cough. Pulm. Pharmacol. Ther. 2007, 20, 402–411. [Google Scholar]
- Gu, Q.; Lee, L.Y. Characterization of acid-signaling in rat vagal pulmonary sensory neurons. Am. J. Physiol. Lung Cell. Mol. Physiol. 2006, 291, L58–L65. [Google Scholar]
- Gu, Q.; Lee, L.Y. Regulation of acid signaling in rat pulmonary sensory neurons by protease-activated receptor-2. Am. J. Physiol. Lung. Cell Mol. Physiol. 2010, 298, L454–L461. [Google Scholar]
- Woolf, C.J.; Salter, M.W. Neuronal plasticity: increasing the gain in pain. Science 2000, 288, 1765–1769. [Google Scholar]
- Treede, R.D.; Jensen, T.S.; Campbell, J.N.; Cruccu, G.; Dostrovsky, J.O.; Griffin, J.W.; Hansson, P.; Hughes, R.; Nurmikko, T.; Serra, J. Neuropathic pain: redefinition and a grading system for clinical and research purposes. Neurology 2008, 70, 1630–1635. [Google Scholar]
- Jensen, T.S.; Madsen, C.S.; Finnerup, N.B. Pharmacology and treatment of neuropathic pains. Curr. Opin. Neurol. 2009, 22, 467–474. [Google Scholar]
- O'Connor, A.B.; Dworkin, R.H. Treatment of neuropathic pain: an overview of recent guidelines. Am. J. Med. 2009, 122, S22–S32. [Google Scholar]
- Harvey, V.L.; Dickenson, A.H. Mechanisms of pain in nonmalignant disease. Curr. Opin. Support Palliat Care. 2008, 2, 133–139. [Google Scholar]
- Jarvis, M.F.; Boyce-Rustay, J.M. Neuropathic pain: models and mechanisms. Curr. Pharm. Des. 2009, 15, 1711–1716. [Google Scholar]
- Sommer, C. Painful neuropathies. Curr. Opin. Neurol. 2003, 16, 623–628. [Google Scholar] [CrossRef] [PubMed]
- Schaible, H.G.; Schmelz, M.; Tegeder, I. Pathophysiology and treatment of pain in joint disease. Adv. Drug Deliv. Rev. 2006, 58, 323–342. [Google Scholar]
- Ohtori, S.; Inoue, G.; Koshi, T.; Ito, T.; Doya, H.; Saito, T.; Moriya, H.; Takahashi, K. Up-regulation of acid-sensing ion channel 3 in dorsal root ganglion neurons following application of nucleus pulposus on nerve root in rats. Spine 2006, 31, 2048–2052. [Google Scholar]
- Mazzuca, M.; Heurteaux, C.; Alloui, A.; Diochot, S.; Baron, A.; Voilley, N.; Blondeau, N.; Escoubas, P.; Gélot, A.; Cupo, A.; Zimmer, A.; Zimmer, A.M.; Eschalier, A.; Lazdunski, M. A tarantula peptide against pain via ASIC1a channels and opioid mechanisms. Nat. Neurosci. 2007, 10, 943–945. [Google Scholar]
- Xiong, Z.G.; Zhu, X.M.; Chu, X.P.; Minami, M.; Hey, J.; Wei, W.L.; MacDonald, J.F.; Wemmie, J.A.; Price, M.P.; Welsh, M.J.; Simon, R.P. Neuroprotection in ischemia: Blocking calcium-permeable acid-sensing ion channels. Cell 2004, 118, 687–698. [Google Scholar]
- Xiong, Z.G.; Chu, X.P.; Simon, R.P. Ca2+-permeable acid-sensing ion channels and ischemic brain injury. J. Membr. Biol. 2006, 209, 59–68. [Google Scholar]
- Friese, M.A.; Craner, M.J.; Etzensperger, R.; Vergo, S.; Wemmie, J.A.; Welsh, M.J.; Vincent, A.; Fugger, L. Acid-sensing ion channel-1 contributes to axonal degeneration in autoimmune inflammation of the central nervous system. Nat. Med. 2007, 13, 1483–1489. [Google Scholar]
- Askwith, C.C.; Cheng, C.; Ikuma, M.; Benson, C.; Price, M.P.; Welsh, M.J. Neuropeptide FF and FMRFamide potentiate acid-evoked currents from sensory neurons and proton-gated DEG/ENaC channels. Neuron 2000, 26, 133–141. [Google Scholar]
- Catarsi, S.; Babinski, K.; Séguéla, P. Selective modulation of heteromeric ASIC proton-gated channels by neuropeptide FF. Neuropharmacology 2001, 41, 592–600. [Google Scholar]
- Deval, E.; Baron, A.; Lingueglia, E.; Mazarguil, H.; Zajac, J.M.; Lazdunski, M. Effects of neuropeptide SF and related peptides on acid sensing ion channel 3 and sensory neuron excitability. Neuropharmacology 2003, 44, 662–671. [Google Scholar]
- Xie, J.; Price, M.P.; Wemmie, J.A.; Askwith, C.C.; Welsh, M.J. ASIC3 and ASIC1 mediate FMRFamide-related peptide enhancement of H+-gated currents in cultured dorsal root ganglion neurons. J. Neurophysiol. 2003, 89, 2459–2465. [Google Scholar]
- Lingueglia, E.; Deval, E.; Lazdunski, M. FMRFamide-gated sodium channel and ASIC channels: A new class of ionotropic receptors for FMRFamide and related peptides. Peptides 2006, 27, 1138–1152. [Google Scholar]
- Yang, H.Y.T.; Tao, T.; Iadarola, M.J. Modulatory role of neuropeptide FF system in nociception and opiate analgesia. Neuropeptides 2008, 42, 1–18. [Google Scholar]
- Allen, N.J.; Attwell, D. Modulation of ASIC channels in rat cerebellar Purkinje neurons by ischaemia-related signals. J. Physiol. 2002, 543, 521–529. [Google Scholar]
- Poirot, O.; Vukicevic, M.; Boesch, A.; Kellenberger, S. Selective regulation of acid-sensing ion channel 1 by serine proteases. J. Biol. Chem. 2004, 279, 38448–38457. [Google Scholar]
- Vukicevic, M.; Weder, G.; Boillat, A.; Boesch, A.; Kellenberger, S. Trypsin cleaves acid-sensing ion channel 1a in a domain that is critical for channel gating. J. Biol. Chem. 2006, 281, 714–722. [Google Scholar]
- Andrey, F.; Tsintsadze, T.; Volkova, T.; Lozovaya, N.; Krishtal, O. Acid sensing ionic channels: modulation by redox reagents. Biochim. Biophys. Acta 2005, 1745, 1–6. [Google Scholar]
- Chu, X.P.; Close, N.; Saugstad, J.A.; Xiong, Z.G. ASIC1a-specific modulation of acid-sensing ion channels in mouse cortical neurons by redox reagents. J. Neurosci. 2006, 26, 5329–5339. [Google Scholar]
- Cadiou, H.; Studer, M.; Jones, N.G.; Smith, E.S.; Ballard, A.; McMahon, S.B.; McNaughton, P.A. Modulation of acid-sensing ion channel activity by nitric oxide. J. Neurosci. 2007, 27, 13251–13260. [Google Scholar]
- Smith, E.S.; Cadiou, H.; McNaughton, P.A. Arachidonic acid potentiates acid-sensing ion channels in rat sensory neurons by a direct action. Neuroscience 2007, 145, 686–698. [Google Scholar]
- Xu, T.L.; Xiong, Z.G. Dynamic regulation of acid-sensing ion channels by extracellular and intracellular modulators. Curr. Med. Chem. 2007, 14, 1753–1763. [Google Scholar]
- Rocha-González, H.I.; Herrejon-Abreu, E.B.; López-Santillán, F.J.; García-López, B.E.; Murbartián, J.; Granados-Soto, V. Acid increases inflammatory pain in rats: effect of local peripheral ASICs inhibitors. Eur. J. Pharmacol. 2009, 603, 56–61. [Google Scholar]
- Voilley, N. Acid-sensing ion channels (ASICs): New targets for the analgesic effects of non-steroid anti-inflammatory drugs (NSAIDs). Curr. Drug Targets Inflamm. Allergy 2004, 3, 71–79. [Google Scholar]
- Escoubas, P.; Bernard, C.; Lambeau, G.; Lazdunski, M.; Darbon, H. Recombinant production and solution structure of PcTx1, the specific peptide inhibitor of ASIC1a proton-gated cation channels. Protein Sci. 2003, 12, 1332–1343. [Google Scholar]
- Diochot, S.; Baron, A.; Rash, L.D.; Deval, E.; Escoubas, P.; Scarzello, S.; Salinas, M.; Lazdunski, M. A new sea anemone peptide, APETx2, inhibits ASIC3, a major acid-sensitive channel in sensory neurons. EMBO J. 2004, 23, 1516–1525. [Google Scholar] [CrossRef] [PubMed]
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