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

Liu, Qin; Tang, Zongxiang; Surdenikova, Lenka; Kim, Seungil; Patel, Krishna; Kim, Andrew; Ren, Feng; Guan, Yun; Weng, Han‐Rong; Geng, Yixun; Undem, Bradley J.; Kollárik, Marián; Chen, Zhou Feng; Anderson, David J.; Dong, Xinzhong

doi:10.1016/j.cell.2009.11.034

Cited by 671 publications

(980 citation statements)

References 45 publications

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“…1 (18)(19)(20). Six different RA challenge compounds were sequentially applied to DRG cultures, and responses from selected neurons are shown in Fig.…”

Section: Resultsmentioning

confidence: 99%

Functional profiling of neurons through cellular neuropharmacology

Teichert

Smith

Raghuraman

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

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We describe a functional profiling strategy to identify and characterize subtypes of neurons present in a peripheral ganglion, which should be extendable to neurons in the CNS. In this study, dissociated dorsal-root ganglion neurons from mice were exposed to various pharmacological agents (challenge compounds), while at the same time the individual responses of >100 neurons were simultaneously monitored by calcium imaging. Each challenge compound elicited responses in only a subset of dorsal-root ganglion neurons. Two general types of challenge compounds were used: agonists of receptors (ionotropic and metabotropic) that alter cytoplasmic calcium concentration (receptor-agonist challenges) and compounds that affect voltage-gated ion channels (membrane-potential challenges). Notably, among the latter are K-channel antagonists, which elicited unexpectedly diverse types of calcium responses in different cells (i.e., phenotypes). We used various challenge compounds to identify several putative neuronal subtypes on the basis of their shared and/or divergent functional, phenotypic profiles. Our results indicate that multiple receptor-agonist and membrane-potential challenges may be applied to a neuronal population to identify, characterize, and discriminate among neuronal subtypes. This experimental approach can uncover constellations of plasma membrane macromolecules that are functionally coupled to confer a specific phenotypic profile on each neuronal subtype. This experimental platform has the potential to bridge a gap between systems and molecular neuroscience with a cellular-focused neuropharmacology, ultimately leading to the identification and functional characterization of all neuronal subtypes at a given locus in the nervous system. sensory neuron | neuronal subpopulation | conotoxin | conopeptide | Fura-2

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“…1 (18)(19)(20). Six different RA challenge compounds were sequentially applied to DRG cultures, and responses from selected neurons are shown in Fig.…”

Section: Resultsmentioning

confidence: 99%

Functional profiling of neurons through cellular neuropharmacology

Teichert

Smith

Raghuraman

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

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“…For example, intracellular signal transduction via PLCβ3 is critical to scratching produced by specific pruritogens (10). Very recently, MrgprA3, one of the members of Mrgpr family of G-protein-coupled receptors (GPCRs), was found to be responsible for mediating chloroquine (CQ)-induced itch responses in TRPV1 neurons (11). These studies suggest that our understanding of the role of TRPV1 neurons as pruriceptors is still limited with respect to how they are able to process responses to a number of different pruritogens.…”

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confidence: 99%

“…Some pruritogens such as histamine or CQ are known to evoke calcium responses in neurons dissociated from dorsal root ganglia (DRG). The calcium responses have been associated with scratching behavioral responses (10,11,24). Thus, we tested the possibility that IQ is also able to evoke Ca 2+ responses in DRG neurons in culture.…”

mentioning

confidence: 99%

“…Because DRG neurons generally rely on external calcium to elicit increases in intracellular calcium when stimulated with algogens or pruritogens (11,25), we examined the contribution of external calcium to IQ-induced calcium responses. In an external Ca 2+ -free condition, the Ca 2+ responses were not affected, but the oscillations following the initial peak were completely abolished (Fig.…”

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confidence: 99%

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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

Kim

Park

Kim

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

102

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Despite its clinical importance, the mechanisms that mediate or generate itch are poorly defined. The identification of pruritic compounds 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 Ca 2+ response revealed 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 receptor potential vanilloid 1 (TRPV1)-expressing neurons for itchassociated responses. Our data provide evidence supporting the hypothesis that there is a specific subset of TRPV1-expressing neurons that is equipped with diverse intracellular mechanisms that respond to histamine, chloroquine, and IQ.

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“…Furthermore, these Mrgprs were also co-expressed with GRP, another neurotransmitter of the "itch pathway" (see above). Importantly, the deletion of the mrgpr gene cluster resulted in an impaired chloriquine response but it did not affect the histamine evoked scratching behavior indicating the role of Mrgprs in non-histaminergic itch [320].…”

Section: Trpa1mentioning

confidence: 99%

TRP Channels and Pruritus

Tóth¹,

Bı́ró²

2013

TOPAINJ

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Itch (pruritus) is one of the most often seen sensory phenomena in clinical practice. Recent neurophysiological findings proposed the existence of a novel pruriceptive system which includes a multitude of pruritogenic (itch-inducing) peripheral mediators, itch-selective pruriceptors, sensory afferent networks, spinal cord neurons, and certain central nervous system regions. In this review, we first introduce major features of the pruriceptive system. We then focus on defining the roles of transient receptor potential (TRP) ion channels in skin-coupled itch and provide compelling evidence that certain thermosensitive TRP channels (especially TRPV1, TRPV3, TRPV4, and TRPA1) are indeed key players in pruritus pathogenesis. Finally, we propose TRP-centered future experimental directions towards the therapeutic targeting of TRP channels in the clinical management of itch.

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

Cited by 671 publications

References 45 publications

Functional profiling of neurons through cellular neuropharmacology

Functional profiling of neurons through cellular neuropharmacology

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

TRP Channels and Pruritus

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