HTR7 Mediates Serotonergic Acute and Chronic Itch

Morita, Takeshi; McClain, Shannan P.; Batia, Lyn; Pellegrino, Maurizio; Wilson, Sarah; Kienzler, Michael A.; Lyman, Kyle A.; Olsen, Anne S.; Wong, J.; Stucky, Cheryl L.; Brem, Rachel B.; Bautista, Diana M.

doi:10.1016/j.neuron.2015.05.044

Cited by 161 publications

(167 citation statements)

References 87 publications

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“…NK1R antagonists were also able to block this antihistamine resistant itch. Consistently, TrpA1 and HTR7 knockout mice both showed impaired scratching and dermatitis phenotypes in the model of topical vitamin D analog MC903 evoked atopic[46]. All the above evidence indicates a pivotal role of TrpA1 in chronic itch in addition to TrpV1.…”

Section: Trp Channels In Chronic Itchmentioning

confidence: 74%

“…Like MrgprA3, activation of TrpA1 by 5-HT7 is also Gβγ dependent but G s coupled 5-HT7 utilizes adenylate cyclase (AC) instead of PLC downstream. TrpA1 knockout significantly attenuated low dose serotonin induced scratching as well as scratching mediated by intradermal selective serotonin reuptake inhibitors (SSRIs) which can increase local serotonin level[46]. Notably high dose serotonin response was not affected in 5-HT7 null mice.…”

Section: Trp Channels and Gpcrs In Itchmentioning

confidence: 99%

“…Bradykinin, IL31 and LTB4 induced itch require both TrpV1 and TrpA1, while most serotonin, TSLP, oxidant and bile acid sensitive neurons also respond to both capsaicin and mustard oil. IL31 population largely overlaps with MrgprA3 population[90], while 5-HT7 receptor expression only partially with histamine and chloroquine receptors[46]. Consistently, MrgprA3 ablation only partially reduce serotonin mediated itch.…”

Section: Primary Itch Populations and Trp Channelsmentioning

confidence: 99%

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Trp channels and itch

Sun

Dong

2015

Semin Immunopathol

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Itch is a unique sensation associated with the scratch reflex. Although the scratch reflex plays a protective role in daily life by removing irritants, chronic itch remains a clinical challenge. Despite urgent clinical need, itch has received relatively little research attention and its mechanisms have remained poorly understood until recently. The goal of the present review is to summarize our current understanding of the mechanisms of acute as well as chronic itch and classifications of the primary itch populations in relationship to transient receptor potential (Trp) channels, which play pivotal roles in multiple somatosensations. The convergent involvement of Trp channels in diverse itch signaling pathways suggests that Trp channels may serve as promising targets for chronic itch treatments.

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Section: Trp Channels In Chronic Itchmentioning

confidence: 74%

Section: Trp Channels and Gpcrs In Itchmentioning

confidence: 99%

Section: Primary Itch Populations and Trp Channelsmentioning

confidence: 99%

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Trp channels and itch

Sun

Dong

2015

Semin Immunopathol

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“…Serotonin is involved in itch associated with dry skin through the 5-HT2 and possibly 5-HT7 receptors [2; 26; 40]. In the imiquimod-induced psoriasis model, we observed that serotonin was expressed by mast cells as well as keratinocytes.…”

Section: Discussionmentioning

confidence: 99%

Mouse model of imiquimod-induced psoriatic itch

Sakai

Sanders

Youssef

et al. 2016

PAIN

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Itch is a major indicator of psoriasis, but the underlying mechanisms behind this symptom are largely unknown. To investigate the neuronal mechanisms of psoriatic itch, we tested whether mice subjected to the imiquimod-induced psoriasis model exhibit itch-associated behaviors. Mice received daily topical applications of imiquimod to the rostral back skin for seven days. Imiquimod-treated mice exhibited a significant increase in spontaneous scratching behavior directed to the treated area as well as touch-evoked scratching (alloknesis). To characterize this model, we measured the mRNA expression levels of pruritogens and itch-relevant receptors/channels using real-time RT-PCR. The mRNA expression of MrgprA3, MrgprC11, and MrgprD decreased gradually over time in the dorsal root ganglion (DRG) cells. There was no significant change in the mRNA expression of TRPV1 or TRPA1 in DRG cells. TRPV4 mRNA expression was transiently increased in the DRG cells, while TRPM8 mRNA was significantly decreased. The mRNA expression levels of histidine decarboxylase and tryptophan hydroxylase 1, as well as the intensity of histamine and serotonin immunoreactivity, were transiently increased in the skin on day 2, returning to baseline by day 7. Histamine H1 receptor (H1R) antagonists, chlorpheniramine and olopatadine, significantly inhibited spontaneous scratching on day 2, but not day 7. Neither chlorpheniramine nor olopatadine affected alloknesis on day 2 or day 7. These results may reflect the limited antipruritic effects of H1R antagonists on human psoriasis. The imiquimod-induced psoriasis model appears to be useful for the investigation of itch and its sensitization in psoriasis.

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“…TRPA1 is also expressed by pruriceptive neurons (pruriceptors) and regulates acute and chronic itch (Liu et al, 2013; Wilson et al, 2011; Wilson et al, 2013a). TRPA1 was regarded as a key signaling molecule for pruritus instead of a receptor of itch, because it is coupled with G-protein-coupled receptors such as MrgprA3 and serotonin receptor HTR7 that can be directly activated by pruritogens (Liu et al, 2009; Morita et al, 2015; Wilson et al, 2011). Although TRPA1 regulates both pain and itch, allyl isothiocyanate (AITC), the most utilized agonist of TRPA1, was thought to primarily elicit pain after intradermal injection (Ross, 2011).…”

Section: Introductionmentioning

confidence: 99%

miRNA-711 Binds and Activates TRPA1 Extracellularly to Evoke Acute and Chronic Pruritus

Han

Liu

Convertino

et al. 2018

Neuron

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SUMMARY Increasing evidence suggests that extracellular miRNAs may serve as biomarkers of diseases, but the physiological relevance of extracellular miRNA is unclear. We find that intradermal cheek injection of miR-711 induces TRPA1-depedent itch (scratching) without pain (wiping) in naïve mice. Extracellular perfusion of miR-711 induces TRPA1 currents in both Trpa1-expressing heterologous cells and native sensory neurons through the core sequence GGGACCC. Computer simulations reveal that the core sequence binds several residues at the extracellular S5-S6 loop of TRPA1, which are critical for TRPA1 activation by miR-711 but not allyl isothiocyanate. Intradermal inoculation of human Myla cells induces lymphoma and chronic itch in immune- deficient mice, associated with increased serum levels of miR-711, secreted from cancer cells. Lymphoma-induced chronic itch is suppressed by miR-711 inhibitor and a blocking peptide that disrupts the miR-711/TRPA1 interaction. Our findings demonstrated an unconventional physiological role of extracellular naked miRNAs as itch mediators and ion channel modulators.

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HTR7 Mediates Serotonergic Acute and Chronic Itch

Cited by 161 publications

References 87 publications

Trp channels and itch

Trp channels and itch

Mouse model of imiquimod-induced psoriatic itch

miRNA-711 Binds and Activates TRPA1 Extracellularly to Evoke Acute and Chronic Pruritus

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