journal club 2015.12.31

Sensory Neuron-Specific GPCR Mrgprs Are Itch Receptors Mediating Chloroquine-Induced Pruritus

Qin Liu,1 Zongxiang Tang,1 Lenka Surdenikova,2,4 Seungil Kim,5 Kush N. Patel,1 Andrew Kim,1 Fei Ru,2 Yun Guan,3
Hao-Jui Weng,1 Yixun Geng,1 Bradley J. Undem,2 Marian Kollarik,2 Zhou-Feng Chen,5 David J. Anderson,6,7
and Xinzhong Dong1,7,*

The cellular and molecular mechanisms mediating
histamine-independent itch in primary sensory
neurons are largely unknown. Itch induced by chloroquine
(CQ) is a common side effect of this widely
used antimalarial drug. Here, we show that Mrgprs,
a family of G protein-coupled receptors expressed
exclusively in peripheral sensory neurons, function
as itch receptors. Mice lacking a cluster of Mrgpr
genes display significant deficits in itch induced by
CQ but not histamine. CQ directly excites sensory
neurons in an Mrgpr-dependent manner. CQ specifically
activates mouse MrgprA3 and human MrgprX1.
Loss- and gain-of-function studies demonstrate
that MrgprA3 is required for CQ responsiveness in
mice. Furthermore, MrgprA3-expressing neurons
respond to histamine and coexpress gastrin-releasing
peptide, a peptide involved in itch sensation,
and MrgprC11. Activation of these neurons with the
MrgprC11-specific agonist BAM8-22 induces itch in
wild-type but not mutant mice. Therefore, Mrgprs
may provide molecular access to itch-selective
neurons and constitute novel targets for itch therapeutics.

2.Sensory Neuron-Specific GPCR Mrgprs

Journal Club 2015.12.18.

Toll-like receptor 4 contributes to chronic itch, alloknesis and spinal astrocyte activation in male mice
Tong Liu , Qingjian Han , Gang Chen , Ya Huang , Lin-Xia Zhao , Temugin Berta ,Yong-Jing Gao , and Ru-Rong Ji

Running title: TLR4 and glial signaling in acute and chronic itch

00006396-900000000-99651

Abstract
Increasing evidence suggests that Toll-like receptor 4 (TLR4) contributes importantly to spinal cord glial activation and chronic pain sensitization; however, its unique role in acute and chronic itch is unclear. In this study, we investigated the involvement of TLR4 in acute and chronic itch models in male mice using both transgenic and pharmacological approaches. Tlr4−/− mice exhibited normal acute itch induced by compound 48/80 and chloroquine, but these mice showed substantial reductions in scratching in chronic itch models of dry skin, induced by acetone and diethyether followed by water (AEW), contact dermatitis, and allergic contact dermatitis on the neck. Intrathecal (spinal) inhibition of TLR4 with lipopolysaccharide Rhodobacter sphaeroides (LPS-RS) did not affect acute itch but suppressed AEW-induced chronic itch. Compound 48/80 and AEW also produced robust alloknesis, a touch-elicited itch in wild-type mice, which was suppressed by intrathecal LPS-RS and Tlr4−/− deletion. AEW induced persistent upregulation of Tlr4 mRNA and increased TLR4 expression in GFAP-expressing astrocytes in spinal cord dorsal horn. AEW also induced TLR4-dependent astrogliosis (GFAP upregulation) in spinal cord. Intrathecal injection of astroglial inhibitor L-α- aminoadipate reduced AEW-induced chronic itch and alloknesis without affecting acute itch. Spinal TLR4 was also necessary for AEW-induced chronic itch in the cheek model. Interestingly, scratching plays an essential role in spinal astrogliosis, since AEW-induced astrogliosis was abrogated by putting Elizabethan Collars on the neck to prevent scratching the itchy skin. Our findings suggest that spinal TLR4 signaling is important for spinal astrocyte activation and astrogliosis that may underlie alloknesis and chronic itch.
Key words: Alloknesis (touch-evoked itch), astrogliosis, dry skin, innate immunity, lipopolysaccharide (LPS), Toll-like receptor 4 (TLR4)

Journal Club 2015.12.11

Involvement of TRPV4 in serotonin-evoked scratching

Tasuku Akiyama1,2, Margaret Ivanov1, Masaki Nagamine1, Auva Davoodi1, Mirela Iodi Carstens1, Akihiko Ikoma3, Ferda Cevikbas3, Cordula Kempkes3, Joerg Buddenkotte3,4, Martin Steinhoff3,4 and E Carstens1

Abstract

Several thermo-sensitive TRP channels (TRPV1, -3; TRPA1) have been implicated in itch. In contrast, the role of transient receptor potential vanilloid type-4 (TRPV4) in itch is unknown. Therefore, we investigated if TRPV4, a temperature-sensitive cation channel, plays an important role in acute itch in mice. Four different pruritogens including serotonin (5-hydroxytrytamine, 5-HT), histamine, SLIGRL (PAR2/MrgprC11 agonist) and chloroquine (MrgprA3 agonist) were intradermally injected and itch-related scratching behavior was assessed. TRPV4 knockout (TRPV4KO) mice exhibited significantly fewer 5-HT-evoked scratching bouts compared to wild-type (WT) mice. Notably, no differences between TRPV4KO and WT mice were observed in the number of scratch bouts elicited by SLIGRL and histamine. Pretreatment with a TRPV4 antagonist significantly attenuated 5-HT-evoked scratching in vivo. Using calcium imaging in cultured primary murine dorsal root ganglion (DRG) neurons, the response of neurons after 5-HT application, but not other pruritogens, was significantly lower in TRPV4KO compared to WT mice. A TRPV4 antagonist significantly suppressed 5-HT-evoked responses in DRG cells from WT mice. Approximately 90% of 5-HT-sensitive DRG neurons were immunoreactive for an antibody to TRPV4, as assessed by calcium imaging. These results indicate that serotonin-induced itch is linked to TRPV4.

Involvement of TRPV4 in serotonin-evoked scratching

Journal club 2015-12-04

Incoherent feed-forward regulatory loops control segregation of C-mechanoreceptors, nociceptors, and pruriceptors.

Abstract

Mammalian skin is innervated by diverse, unmyelinated C fibers that are associated with senses of pain, itch, temperature, or touch. A key developmental question is how this neuronal cell diversity is generated during development. We reported previously that the runt domain transcription factor Runx1 is required to coordinate the development of these unmyelinated cutaneous sensory neurons, including VGLUT3(+) low-threshold c-mechanoreceptors (CLTMs), MrgprD(+) polymodal nociceptors, MrgprA3(+) pruriceptors, MrgprB4(+) c-mechanoreceptors, and others. However, how these Runx1-dependent cutaneous sensory neurons are further segregated is poorly illustrated. Here, we find that the Runx1-dependent transcription factor gene Zfp521 is expressed in, and required for establishing molecular features that define, VGLUT3(+) CLTMs. Furthermore, Runx1 and Zfp521 form a classic incoherent feedforward loop (I-FFL) in controlling molecular identities that normally belong to MrgprD(+) neurons, with Runx1 and Zfp51 playing activator and repressor roles, respectively (in genetic terms). A knock-out of Zfp521 allows prospective VGLUT3 lineage neurons to acquire MrgprD(+) neuron identities. Furthermore, Runx1 might form other I-FFLs to regulate the expression of MrgprA3 and MrgprB4, a mechanism preventing these genes from being expressed in Runx1-persistent VGLUT3(+) and MrgprD(+) neurons. The evolvement of these I-FFLs provides an explanation for how modality-selective sensory subtypes are formed during development and may also have intriguing implications for sensory neuron evolution and sensory coding

KEYWORDS:

Runx1; Zfp521; low-threshold c-mechanoreceptors; nociceptors; pruriceptors; sensory subtype specification

 

5317.full

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