Abstract
Mas1-related G-protein-coupled receptors (Mrgprs), comprising more than 50 distinct members, are specifically expressed in primary sensory neurons. Reflecting the diversity and specificity of stimuli they detect, Mrgprs are involved in pain, touch, and itch-related behaviors. Sensory–neuron-specific acid-sensing ion channel 3 (ASIC3) is essential for touch and inflammatory pain, but mice lacking ASIC3 have complex behavioral alterations in various modalities of pain and touch. To understand whether Mrgprs are involved in complex behavioral alterations found in ASIC3-deficient mice, we examined Mrgpr gene expression in ASIC3−/− mice. Only MrgprB4 expression has shown significant change. MrgprB4 expression was increased in ASIC3−/− dorsal root ganglia (DRG) but decreased in ASIC3−/− trigeminal ganglia. The distinct alterations in DRG and trigeminal ganglia imply that MrgprB4 could have multiple functions. Given that MrgprB4 is expressed in neurons that may detect gentle touch and that ASIC3−/− mice have altered sensitivity of mechanoreceptors for light touch, the expression change of MrgprB4 is more likely related to the altered touch behaviors of ASIC3−/− mice.
Similar content being viewed by others
References
Alvarez de la Rosa D, Zhang P, Shao D, White F, Canessa CM (2002) Functional implications of the localization and activity of acid-sensitive channels in rat peripheral nervous system. PNAS 99:2326–2331
Bereiter DA, Hargreaves KM, Hu JW (2009) Tirgeminal mechanisms of nociception: peripheral and brainstem organization. In: Basbaum AI, Bushnell MC (eds) Science of pain. Elsevier, San Diego, CA, pp 435–460
Bender E, Buist A, Jurzak M, Langlois X, Baggerman G, Verhasselt P, Ercken M, Guo HQ, Wintmolders C, Van den Wyngaert I, Van Oers I, Schoofs L, Luyten W (2002) Characterization of an orphan G protein-coupled receptor localized in the dorsal root ganglia reveals adenine as a signaling molecule. Proc Natl Acad Sci U S A 99:8573–8578
Breese NM, George AC, Pauers LE, Stucky CL (2005) Peripheral inflammation selectively increases TRPV1 function in IB4-positive sensory neurons from adult mouse. Pain 115:37–49
Caterina MJ, Schumacher MA, Tominaga M, Rosen TA, Levine JD, Julius D (1997) The capsacicin receptor: a heat-activated ion channel in the pain pathway. Nature 389:816–824
Chen CC, England S, Akopian AN, Wood JN (1998) A sensory neuron-specific, proton-gated ion channel. PNAS 95:10240–10245
Chen CC, Wong CW (2013) Neurosensory mechanotransduction through acid-sensing ion channels. J Cell Mol Med 17:337–349
Chen CC, Zimmer A, Sun WH, Hall J, Browstein MJ, Zimmer A (2002) A role for ASIC3 in the modulation of high-intensity pain stimuli. PNAS 99:8992–8997
Cai Q, Jiang J, Chen T, Hong Y (2007) Sensory neuron-specific receptor agonist BAM8-22 inhibits the development and expression of tolerance to morphine in rats. Behav Brain Res 178:154–159
Cox PJ, Pitcher T, Trim SA, Bell CH, Qin W, Kinloch RA (2008) The effect of deletion of the orphan G-protein coupled receptor (GPCR) gene MrgE on pain-like behaviours in mice. Mol Pain 4:2
Crozier RA, Ajit SK, Kaftan EJ, Pausch MH (2007) MrgprD activation inhibits KCNQ/M-currents and contributes to enhanced neuronal excitability. J Neurosci 27:4492–4496
Davis AM (2000) Neurotrophic factor requirements of developing sensory neurons. In: Wood JN (ed) Molecular basis of pain induction. Wiley-Liss, NY, pp 23–42
Deval E, Noel J, Lay N, Alloui A, Diochot S, Friend V, Jodar M, Lazdunski M, Lingueglia E (2008) ASIC3, a sensor of acidic and primary inflammatory pain. EMBO J 27:3047–3055
Dirajlal S, Pauers LE, Stucky CL (2003) Differential response properties of IB(4)-positive and -negative unmyelinated sensory neurons to protons and capsaicin. J Neurophysiol 89:513–524
Dong X, Han S, Zylka MJ, Simon MI, Anderson DJ (2001) A diverse family of GPCRs expressed in specific subsets of nociceptive sensory neurons. Cell 106:619–632
Ferri GL, Sabani A, Abelli L, Polak JM, Dahl D, Portier MM (1990) Neuronal intermediate filaments in rat dorsal root ganglia: differential distribution of peripherin and neurofilament protein immunoreactivity and effect of capsaicin. Brain Res 515:331–335
Grazzini E, Puma C, Roy MO, Yu XH, O’Donnell D, Schmidt R, Dautrey S, Ducharme J, Perkins M, Panetta R, Laird JMA, Ahmad S, Lembo PMC (2004) Sensory neuron-specific receptor activation elicits central and peripheral nociceptive effects in rats. Proc Natl Acad Sci U S A 101:7175–7180
Goldstein ME, House SB, Gainer H (1991) NF-L and peripherin immunoreactivities define distinct classes of rat sensory ganglion cells. J Neurosci Res 30:92–104
Guo A, Vulchanova L, Wang J, Li X, Elde R (1999) Immunocytochemical localization of the vanilloid receptor 1 (VR1): relationship to neuropeptides, the P2X3 purinoceptorand IB4 binding sites. Eur J Neurosci 11:946–958
Han SK, Dong X, Hwang JI, Zylka MJ, Anderson DJ, Simon MI (2002) Orphan G protein- coupled receptors MrgprA1 and C11 are distinctively activated by RF- amide- related peptides through the Gαq/11 pathway. Proc Natl Acad Sci U S A 99:14740–14745
Hong Y, Dai P, Jiang J, Zeng X (2004) Dual effects of intrathecal BAM22 on nociceptive responses in acute and persistent pain-potential function of a novel receptor. Br J Pharmacol 141:423–430
Huang CW, Tzeng JN, Chen YJ, Tsai WF, Chen CC, Sun WH (2007) Nociceptors of dorsal root ganglion express proton-sensing G-protein-coupled receptors. Mol Cell Neurosci 36:195–210
Ichikawa H, Sugimoto T (2002) The co-expression of ASIC3 with calcitonin gene-related peptide and parvalbumin in the rat trigeminal ganglion. Brain Res 943:287–291
Krishtal OA (2003) The ASICs: signaling molecules? Modulators? Trend Neurosci 126:477–483
Lawson SN, Waddell PJ (1991) Soma neurofilament immunoreactivity is related to cell size and fibre conduction velocity in rat primary sensory neurons. J Physiol (London) 435:41–63
Lazarov NE (2002) Comparative analysis of the chemical neuroanatomy of the mammalian trigeminal ganglion and mesencephalic trigeminal nucleus. Prog Neurol 66:19–59
Lee CJ, Bardoni R, Tong CK, Engelman HS, Joseph DJ, Magherini PC, MacDermott AB (2002) Functional expression of AMPA receptors on central terminals rat dorsal root ganglion neurons and presynaptic inhibition of glutamate release. Neuron 36:135–146
Lembo PM, Grazzini E, Groblewski T, O'Donnell D, Roy MO, Zhang J, Hoffert C, Cao J, Schmidt R, Pelletier M, Labarre M, Gosselin M, Fortin Y, Banville D, Shen SH, Strom P, Payza K, Dray A, Walker P, Ahmad S (2002) Proenkephalin A gene products activate a new family of sensory neuron-specific GPCRs. Nat Neurosci 5:201–209
Leung CL, Sun D, Liem RKH (1999) The intermediate filament protein peripherin is the specific interaction partner of mouse BPAG1-n (dystonin) in neurons. J Cell Biol 144:435–446
Lin SY, Chang WJ, Lin CS, Huang CY, Wang HF, Sun WH (2011) Serotonin receptor 5-HT2B mediates serotonin-induced mechanical hyperalgesia. J Neurosci 31:1410–18
Lingueglia E (2007) Acid-sensing ion channels in sensory perception. J Biol Chem 282:17325–17329
Liu Q, Tang Z, Surdenikova L, Kim S, Patel KN, Kim A, Ru F, Guan Y, Weng HJ, Geng Y, Undem BJ, Kollarik M, Chen ZF, Anderson DJ, Dong X (2009) Sensory neuron-specific GPCR Mrgprs are itch receptors mediating chloroquine-induced pruritus. Cell 139:1353–1365
Liu Q, Vrontou S, Rice FL, Zylka MJ, Dong X, Anderson DJ (2007) Molecular genetic visualization of a rare subset of unmyelinated sensory neurons that may detect gentle touch. Nat Neurosci 10:946–948
Mogil JS, Breese NM, Witty M-F, Ritchie J, Rainville M-L, Ase A, Abbadi N, Stucky CL, Seguela P (2005) Transgenic expression of a dominant-negative ASIC3 subunit leads to increased sensitivity to mechanical and inflammatory stimuli. J Neurosci 25:9893–9901
Molliver DC, Wright DE, Leitner ML, Parsadanian AS, Doster K, Wen D, Yan Q, Snider WD (1997) IB4-binding DRG neurons switch from NGF to GDNF dependence in early postnatal life. Neuron 19:849–861
Molliver DC, Immke DC, Fierro L, Pare M, Rice FL, McCleskey EW (2005) ASIC3, an acid-sensing ion channel, is expressed in metaboreceptive sensory neurons. Mol Pain 1:35–48
Mosconi T, Snider WD, Jacquin MF (2001) Neurotrophin receptor expression in retrogradely labeled trigeminal nociceptors-comparisons with spinal nociceptors. Somatosens Mot Res 18:312–321
Nordin M (1990) Low-threshold mechanoreceptive and nociceptive units with unmyelinated (C) fibres in the human supraorbital nerve. J Physiol (London) 426:229–240
Olausson H, Lamarre Y, Backlund H, Morin C, Wallin BG, Starck G, Ekholm S, Strigo I, Worsley K, Vallbo ÅB, Bushnell MC (2002) Unmyelinated tactile afferents signal touch and project to insular cortex. Nat Neurosci 5:900–904
Pearson ES, Hartley HO (1976) Biometrika tables for statisticians. Biometrika Trust University Press. p289
Potrebic S, Ahn AH, Skinner K, Fields HL, Basbaum AI (2003) Peptidergic nociceptors of both trigeminal and dorsal root ganglia express serotonin 1D receptors: implications for the selective antimigraine action of triptans. J Neurosci 23:10988–10997
Price MP, Mcllwrath SL, Xie J, Cheng C, Qiao J, Tarr DE, Sluka KA, Brennan TJ, Lewin GR, Welsh MJ (2001) The DRASIC cation channel contributes to the detection of cutaneous touch and acid stimuli in mice. Neuron 32:1071–1083
Robas N, Mead E, Fidock M (2003) MrgprX2 is a high potency cortistatin receptor expressed in dorsal root ganglion. J Biol Chem 278:44400–44404
Shinohara T, Harada M, Ogi K, Maruyama M, Fujii R, Tanaka H, Fukusumi S, Komatsu H, Hosoya M, Noguchi Y, Watanabe T, Moriya T, Itoh Y, Hinuma S (2004) Identification of a G protein- coupled receptor specifically responsive to β-alanine. J Biol Chem 279:23559–23564
Silos-Santiago I (2000) Neurotrophic signaling and sensory neuron survival and function. In: Wood JN (ed) Molecular basis of pain induction. Wiley-Liss, NY, pp 43–64
Sluka KA, Price MP, Breese NM, Stucky CL, Wemmie JA, Welsh MJ (2003) Chronic hyperalgesia induced by repeated acid injections in muscle is abolished by the loss of ASIC3, but not ASIC1. Pain 106:229–239
Sluka KA, Radhakrishnan R, Benson CJ, Eshcol JO, Price MP, Babinski K, Audette KM, Yeomans DC, Wilson SP (2007) ASIC3 in muscle mediates mechanical, but not heat, hyperalgesia associated with muscle inflammation. Pain 129:102–112
Stucky CL, Lewin GR (1999) Isolectin B(4)-positive and -negative nociceptors are functionally distinct. J Neurosci 19:6497–6505
Sutherland SP, Benson CJ, Adelman JP, McCleskey EW (2001) Acid-sensing ion channel 3 matches the acid-gated current in cardiac ischemia-sensing neurons. Proc Natl Acad Sci U S A 98:711–716
Snider WD, McMahon SB (1998) Tacking pain at the source: new ideas about nociceptors. Neuron 20:629–632
Tominaga M, Caterina MJ, Malmberg AB, Rosen TA, Gilbert H, Skinner K, Raumann BE, Basbaum AI, Julius D (1998) The cloned capsaicin receptor integrates multiple pain-producing stimuli. Neuron 21:531–543
Ugawa S, Ueda T, Yamamura H, Shimada S (2005) In situ hybridization evidence for the coexistence of ASIC and TRPV1 within rat single sensory neurons. Mol Brain Res 136:125–133
Vallbo ÅB, Olausson H, Wessberg J, Norrsell U (1993) A system of unmyelinated afferents for innocuous mechanoreception in the human skin. Brain Res 628:301–304
Vallbo ÅB, Olausson H, Wessberg J (1999) Unmyelinated afferents constitute a second system coding tactile stimuli of the human hairy skin. J Neurophysiol 81:2753–2763
Vrontou S, Wong AM, Rau KK, Koerber HR, Anderson DJ (2013) Genetic identification of C fibres that detect massage-like stroking of hairy skin in vivo. Nature 493:669–673
Waldmann R, Bassilana F, de Weille J, Champigny G, Heurteaux C, Lazdunski M (1997a) Molecular cloning of a non-inactivating proton-gated Na + channel specific for sensory neurons. J Biol Chem 272:20975–20978
Waldmann R, Champigny G, Bassilana F, Heurteaux C, Lazdunski M (1997b) A proton-gated cation channel involved in acid-sensing. Nature 386:173–177
Wu WL, Wang CH, Huang E, Chen CC (2009) Asic3−/− female mice with hearing deficit affects social development of pups. PLoS One 4:e6508
Yagi I, Wenk HN, Naves LA, McCleskey EW (2006) Sustained currents through ASIC3 ion channels at the modest pH changes that occur during myocardial ischemia. Circ Res 99:501–509
Yen YT, Tu PH, Chen CJ, Lin YW, Hsieh ST, Chen CC (2009) Role of acid-sensing ion channel 3 in sub-acute-phase inflammation. Mol Pain 5:1
Zwick M, Davis BM, Woodbury CJ, Burkett JN, Koerber HR, Simpson JF, Alberts KM (2002) Glial cell line-derived neurotrophic factor is a survival factor for isolectin B4-positive, but not vanilloid receptor 1-positive, neurons in the mouse. J Neurosci 22:4057–4065
Zylka MJ, Dong X, Southwell AL, Anderson DJ (2003) A typical expansion in mice of the sensory neuron-specific Mrgpr G protein-coupled receptor family. Proc Natl Acad Sci U S A 100:10043–10048
Zylka MJ, Rice FL, Anderson DJ (2005) Topographically distinct epidermal nociceptive circuits revealed by axonal tracers targeted to Mrgprd. Neuron 45:17–25
Acknowledgments
We thank the support of the Institute of Neuroscience at National Yang Ming University for the calcium imaging system. This work was supported by funds from National Science Council, Taiwan (grant no. NSC101-2321-B-008-001), and from National Central University and Landseed Hospital, Taiwan (grant no. NCU-LSH-101-A-002).
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Huang, YH., Chang, CY., Chen, CC. et al. Distinct Expression of Mas1-Related G-Protein-Coupled Receptor B4 in Dorsal Root and Trigeminal Ganglia—Implications for Altered Behaviors in Acid-Sensing Ion Channel 3-Deficient Mice. J Mol Neurosci 51, 820–834 (2013). https://doi.org/10.1007/s12031-013-0070-0
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s12031-013-0070-0