Journal club 2013-03-15

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Analysis of cellular and behavioral responses to imiquimod reveals a unique itch pathway in transient receptor potential vanilloid 1 (TRPV1)-expressing neurons

pnas.201019755

pnas.201019755SI

Se-Jeong Kima,b,1, Goon Ho Parka,1, Donghoon Kimb, Jaekwang Leec, Hyejung Mina, Estelle Walla, C. Justin Leec, Melvin I. Simona,2, Sung Joong Leeb,2, and Sang-Kyou Hana,2

aDepartment of Pharmacology, University of California at San Diego, La Jolla, CA 92093; bDepartment of Neuroscience, Dental Research Institute, and Brain Korea21, School of Dentistry, Seoul National University, Seoul 110-749, Republic of Korea; cCenter for Functional Connectomics, Korea Institute of Science and Technology, Seoul 136-791, Republic of Korea

Contributed by Melvin I. Simon, January 5, 2011 (sent for review November 7, 2010)

Despite its clinical importance, the mechanisms that mediate or generate itch are poorly defined. The identification of pruritic com- pounds offers insight into understanding the molecular and cellular basis of itch. Imiquimod (IQ) is an agonist of Toll-like receptor 7 (TLR7) used to treat various infectious skin diseases such as genital warts, keratosis, and basal cell carcinoma. Itch is reportedly one of the major side effects developed during IQ treatments. We found that IQ acts as a potent itch-evoking compound (pruritogen) in mice via direct excitation of sensory neurons. Combined studies of scratching behavior, patch-clamp recording, and Ca2+ response re- vealed the existence of a unique intracellular mechanism, which is independent of TLR7 as well as different from the mechanisms exploited by other well-characterized pruritogens. Nevertheless, as for other pruritogens, IQ requires the presence of transient re- ceptor potential vanilloid 1 (TRPV1)-expressing neurons for itch- associated responses. Our data provide evidence supporting the hypothesis that there is a specific subset of TRPV1-expressing neu- rons that is equipped with diverse intracellular mechanisms that respond to histamine, chloroquine, and IQ.

Journal club 2013-03-05

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8612.full

J Neurosci. 2009 Jul 1;29(26):8612-9. doi: 10.1523/JNEUROSCI.1057-09.2009.

Mrgprd enhances excitability in specific populations of cutaneous murine polymodal nociceptors.

Source

Department of Neurobiology, University of Pittsburgh, Pittsburgh, Pennsylvania 15261, USA.

Abstract

The Mas-related G protein-coupled receptor D (Mrgprd) is selectively expressed in nonpeptidergic nociceptors that innervate the outer layers of mammalian skin. The function of Mrgprd in nociceptive neurons and the physiologically relevant somatosensory stimuli that activate Mrgprd-expressing (Mrgprd(+)) neurons are currently unknown. To address these issues, we studied three Mrgprd knock-in mouse lines using an ex vivo somatosensory preparation to examine the role of the Mrgprd receptor and Mrgprd(+) afferents in cutaneous somatosensation. In mouse hairy skin, Mrgprd, as marked by expression of green fluorescent protein reporters, was expressed predominantly in the population of nonpeptidergic, TRPV1-negative, C-polymodal nociceptors. In mice lacking Mrgprd, this population of nociceptors exhibited decreased sensitivity to cold, heat, and mechanical stimuli. Additionally, in vitro patch-clamp studies were performed on cultured dorsal root ganglion neurons from Mrgprd(-/-) and Mrgprd(+/-) mice. These studies revealed a higher rheobase in neurons from Mrgprd(-/-) mice than from Mrgprd(+/-) mice. Furthermore, the application of the Mrgprd ligand beta-alanine significantly reduced the rheobase and increased the firing rate in neurons from Mrgprd(+/-) mice but was without effect in neurons from Mrgprd(-/-) mice. Our results demonstrate that Mrgprd influences the excitability of polymodal nonpeptidergic nociceptors to mechanical and thermal stimuli.

PMID:
19571152
[PubMed – indexed for MEDLINE

Journal club 2013-02-22

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A subpopulation of nociceptors specifically linked to itch

nn.3289-S1, nn.3289

Liang Han1, Chao Ma2,3, Qin Liu1,4, Hao-Jui Weng1,4, Yiyuan Cui5, Zongxiang Tang1,4, Yushin Kim1, Hong Nie3,6, Lintao Qu3, Kush N Patel1,4, Zhe Li1, Benjamin McNeil1, Shaoqiu He7, Yun Guan7, Bo Xiao5, Robert H LaMotte3 & Xinzhong Dong1,4

Itch-specific neurons have been sought for decades. The existence of such neurons has been doubted recently as a result of the observation that itch-mediating neurons also respond to painful stimuli. We genetically labeled and manipulated MrgprA3+ neurons in the dorsal root ganglion (DRG) and found that they exclusively innervated the epidermis of the skin and responded to multiple pruritogens. Ablation of MrgprA3+ neurons led to substantial reductions in scratching evoked by multiple pruritogens and occurring spontaneously under chronic itch conditions, whereas pain sensitivity remained intact. Notably, mice in which TRPV1 was exclusively expressed in MrgprA3+ neurons exhibited itch, but not pain, behavior in response to capsaicin. Although MrgprA3+ neurons were sensitive to noxious heat, activation of TRPV1 in these neurons by noxious heat did not alter pain behavior. These data suggest that MrgprA3 defines a specific subpopulation of DRG neurons mediating itch. Our study opens new avenues for studying itch and developing anti-pruritic therapies.

Journal club 2013-02-01

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A Heat-Sensitive TRP Channel Expressed in Keratinocytes

Andrea M. Peier,1 Alison J. Reeve,2 David A. Andersson,2 Aziz Moqrich,3 Taryn J. Earley,3 Anne C. Hergarden,1 Gina M. Story,3 Sian Colley,2 John B. Hogenesch,1 Peter McIntyre,2 Stuart Bevan,2 Ardem Patapoutian1,3*

1073140s

Science-2002-Peier-2046-9

Mechanical and thermal cues stimulate a specialized group of sensory neurons that terminate in the skin. Three members of the transient receptor potential (TRP) family of channels are expressed in subsets of these neurons and are activated at distinct physiological temperatures. Here, we describe the cloning and characterization of a novel thermosensitive TRP channel. TRPV3 has a unique threshold: It is activated at innocuous (warm) temperatures and shows an increased response at noxious temperatures. TRPV3 is specifically expressed in keratinocytes; hence, skin cells are capable of detecting heat via molecules similar to those in heat-sensing neurons.

Journal club 2013-01-25

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1744-8069-8-75

Mol Pain. 2012 Sep 27;8:75. doi: 10.1186/1744-8069-8-75.

Prostaglandin metabolite induces inhibition of TRPA1 and channel-dependent nociception.

Source

Department of Anesthesiology, Washington University Pain Center, St, Louis, MO 63110, USA. storyg@wustl.edu.

ABSTRACT:

BACKGROUND:

The Transient Receptor Potential (TRP) ion channel TRPA1 is a key player in pain pathways. Irritant chemicals activate ion channel TRPA1 via covalent modification of N-terminal cysteines. We and others have shown that 15-Deoxy-Δ12, 14-prostaglandin J2 (15d-PGJ2) similarly activates TRPA1 and causes channel-dependent nociception. Paradoxically, 15d-PGJ2 can also be anti-nociceptive in several pain models. Here we hypothesized that activation and subsequent desensitization of TRPA1 in dorsal root ganglion (DRG) neurons underlies the anti-nociceptive property of 15d-PGJ2. To investigate this, we utilized a battery of behavioral assays and intracellular Ca2+ imaging in DRG neurons to test if pre-treatment with 15d-PGJ2 inhibited TRPA1 to subsequent stimulation.

RESULTS:

Intraplantar pre-injection of 15d-PGJ2, in contrast to mustard oil (AITC), attenuated acute nocifensive responses to subsequent injections of 15d-PGJ2 and AITC, but not capsaicin (CAP). Intraplantar 15d-PGJ2-administered after the induction of inflammation-reduced mechanical hypersensitivity in the Complete Freund’s Adjuvant (CFA) model for up to 2 h post-injection. The 15d-PGJ2-mediated reduction in mechanical hypersensitivity is dependent on TRPA1, as this effect was absent in TRPA1 knockout mice. Ca2+ imaging studies of DRG neurons demonstrated that 15d-PGJ2 pre-exposure reduced the magnitude and number of neuronal responses to AITC, but not CAP. AITC responses were not reduced when neurons were pre-exposed to 15d-PGJ2 combined with HC-030031 (TRPA1 antagonist), demonstrating that inhibitory effects of 15d-PGJ2 depend on TRPA1 activation. Single daily doses of 15d-PGJ2, administered during the course of 4 days in the CFA model, effectively reversed mechanical hypersensitivity without apparent tolerance or toxicity.

CONCLUSIONS:

Taken together, our data support the hypothesis that 15d-PGJ2 induces activation followed by persistent inhibition of TRPA1 channels in DRG sensory neurons in vitro and in vivo. Moreover, we demonstrate novel evidence that 15d-PGJ2 is analgesic in mouse models of pain via a TRPA1-dependent mechanism. Collectively, our studies support that TRPA1 agonists may be useful as pain therapeutics.

Journal club 2013-01-14

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Mechanisms of Itch Evoked by ß-Alanine

Dong

Qin Liu,1,2 Parul Sikand,3 Chao Ma,3 Zongxiang Tang,1,2 Liang Han,1 Zhe Li,1 Shuohao Sun,1 Robert H. LaMotte,3
and Xinzhong Dong1,2
1The Solomon H. Snyder Department of Neuroscience, Center for Sensory Biology, and 2Howard Hughes Medical Institute, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, and 3Department of Anesthesiology, Yale University School of Medicine, New Haven, Connecticut 06520

ß-alanine, a popular supplement for muscle building, induces itch and tingling after consumption, but the underlying molecular and neural mechanisms are obscure. Here we show that, in mice,

Journal club 2012-12-27

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10.1177_0022034511412074

J Dent Res. 2011 Sep;90(9):1098-102. doi: 10.1177/0022034511412074. Epub 2011 Jun 10.

Cold suppresses agonist-induced activation of TRPV1.

Source

Department of Neural and Pain Sciences, University of Maryland Dental School, Program in Neuroscience, 650 W. Baltimore Street, Baltimore, MD 21201, USA. mchung@umaryland.edu

Abstract

Cold therapy is frequently used to reduce pain and edema following acute injury or surgery such as tooth extraction. However, the neurobiological mechanisms of cold therapy are not completely understood. Transient receptor potential vanilloid 1 (TRPV1) is a capsaicin- and heat-gated nociceptive ion channel implicated in thermosensation and pathological pain under conditions of inflammation or injury. Although capsaicin-induced nociception, neuropeptide release, and ionic currents are suppressed by cold, it is not known if cold suppresses agonist-induced activation of recombinant TRPV1. We demonstrate that cold strongly suppressed the activation of recombinant TRPV1 by multiple agonists and capsaicin-evoked currents in trigeminal ganglia neurons under normal and phosphorylated conditions. Cold-induced suppression was partially impaired in a TRPV1 mutant that lacked heat-mediated activation and potentiation. These results suggest that cold-induced suppression of TRPV1 may share a common molecular basis with heat-induced potentiation, and that allosteric inhibition may contribute, in part, to the cold-induced suppression. We also show that combination of cold and a specific antagonist of TRPV1 can produce an additive suppression. Our results provide a mechanistic basis for cold therapy and may enhance anti-nociceptive approaches that target TRPV1 for managing pain under inflammation and tissue injury, including that from tooth extraction.

PMID:
21666106
[PubMed – indexed for MEDLINE]
PMCID:
PMC3169882

Free PMC Article

Journal club 2012-12-07

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TRPA1 underlies a sensing mechanism for O2

nchembio.640 , nchembio.640-S1

nobuaki takahashi1–3, tomoyuki Kuwaki4, shigeki Kiyonaka1,2,5, tomohiro numata1,2, daisuke Kozai1,2, Yusuke Mizuno1,2, shinichiro Yamamoto1,2, shinji naito6, ellen Knevels7,8, peter Carmeliet7,8, toru Oga9, shuji Kaneko10, seiji suga1, toshiki nokami1, Jun-ichi Yoshida1 & Yasuo Mori1,2,5*

Oxygen (O2) is a prerequisite for cellular respiration in aerobic organisms but also elicits toxicity. To understand how animals cope with the ambivalent physiological nature of O2, it is critical to elucidate the molecular mechanisms responsible for O2 sens- ing. Here our systematic evaluation of transient receptor potential (TRP) cation channels using reactive disulfides with differ- ent redox potentials reveals the capability of TRPA1 to sense O2. O2 sensing is based upon disparate processes: whereas prolyl hydroxylases (PHDs) exert O2-dependent inhibition on TRPA1 activity in normoxia, direct O2 action overrides the inhibition via the prominent sensitivity of TRPA1 to cysteine-mediated oxidation in hyperoxia. Unexpectedly, TRPA1 is activated through relief from the same PHD-mediated inhibition in hypoxia. In mice, disruption of the Trpa1 gene abolishes hyperoxia- and hypoxia-induced cationic currents in vagal and sensory neurons and thereby impedes enhancement of in vivo vagal discharges induced by hyperoxia and hypoxia. The results suggest a new O2-sensing mechanism mediated by TRPA1.

Journal club 2012-11-30

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1-s2.0-S0304395910003246-main

Pain. 2010 Aug;150(2):340-50. Epub 2010 Jun 12.

TRPM8, but not TRPA1, is required for neural and behavioral responses to acute noxious cold temperatures and cold-mimetics in vivo.

Source

Neuroscience Graduate Program, Department of Biological Sciences, University of Southern California, Los Angeles, CA 90089, USA.

Abstract

Somatosensory neurons detect environmental stimuli, converting external cues into neural activity that is relayed first to second-order neurons in the spinal cord. The detection of cold is proposed to be mediated by the ion channels TRPM8 and TRPA1. However, there is significant debate regarding the role of each channel in cold-evoked pain, complicating their potential as drug targets for conditions such as cold allodynia and hyperalgesia. To address this debate, we generated mice lacking functional copies of both channels and examined behaviors and neural activity in response to painful cold and noxious cooling compounds. Whereas normal mice display a robust preference for warmth over cold, both TRPM8-null (TRPM8(-/-)) and TRPM8/TRPA1 double-knockout mice (DKO) display no preference until temperatures reach the extreme noxious range. Additionally, in contrast to wildtype mice that avoid touching cold surfaces, mice lacking TRPM8 channels display no such avoidance and explore noxious cold surfaces, even at 5 degrees C. Furthermore, nocifensive behaviors to the cold-mimetic icilin are absent in TRPM8(-/-) and DKO mice, but are retained in TRPA1-nulls (TRPA1(-/-)). Finally, neural activity, measured by expression of the immediate-early gene c-fos, evoked by hindpaw stimulation with noxious cold, menthol, or icilin is reduced in TRPM8(-/-) and DKO mice, but not in TRPA1(-/-) animals. Thus our results show that noxious cold signaling is exclusive to TRPM8, mediating neural and behavioral responses to cold and cold-mimetics, and that TRPA1 is not required for acute cold pain in mammals.

Copyright (c) 2010 International Association for the Study of Pain. Published by Elsevier B.V. All rights reserved.

Journal club 2012-11-09

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Piezo1 and Piezo2 Are Essential Components of Distinct Mechanically Activated Cation Channels

Coste-SOM
Filename : coste-som.pdf (10 MB)
Caption :
sci
Filename : sci.pdf (1 MB)
Caption :

Bertrand Coste,1 Jayanti Mathur,2 Manuela Schmidt,1 Taryn J. Earley,1 Sanjeev Ranade,1 Matt J. Petrus,2 Adrienne E. Dubin,1 Ardem Patapoutian1,2*

Mechanical stimuli drive many physiological processes, including touch and pain sensation, hearing, and blood pressure regulation. Mechanically activated (MA) cation channel activities have been recorded in many cells, but the responsible molecules have not been identified.
We characterized a rapidly adapting MA current in a mouse neuroblastoma cell line. Expression profiling and RNA interference knockdown of candidate genes identified Piezo1 (Fam38A) to be required for MA currents in these cells. Piezo1 and related Piezo2 (Fam38B) are vertebrate multipass transmembrane proteins with homologs in invertebrates, plants, and protozoa. Overexpression of mouse Piezo1 or Piezo2 induced two kinetically distinct MA currents. Piezos are expressed in several tissues, and knockdown of Piezo2 in dorsal root ganglia neurons specifically reduced rapidly adapting MA currents. We propose that Piezos are components of MA cation channels.

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