Journal Club 2014-04-25

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Pirt, a TRPV1 Modulator, Is Required for Histamine-Dependent and -Independent Itch

Abstract

Itch, or pruritus, is an important clinical problem whose molecular basis has yet to be understood. Recent work has begun to identify genes that contribute to detecting itch at the molecular level. Here we show that Pirt, known to play a vital part in sensing pain through modulation of the transient receptor potential vanilloid 1 (TRPV1) channel, is also necessary for proper itch sensation. Pirt−/− mice exhibit deficits in cellular and behavioral responses to various itch-inducing compounds, or pruritogens. Pirt contributes to both histaminergic and nonhistaminergic itch and, crucially, is involved in forms of itch that are both TRPV1-dependent and -independent. Our findings demonstrate that the function of Pirt extends beyond nociception via TRPV1 regulation to its role as a critical component in several itch signaling pathways

http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0020559

Journal Club 2014-04-11

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BEHAVIORAL MODEL OF ITCH, ALLOKNESIS, PAIN AND ALLODYNIA IN THE LOWER HINDLIMB AND CORRELATIVE RESPONSES
OF LUMBAR DORSAL HORN NEURONS IN THE MOUSE

T. AKIYAMA, M. NAGAMINE, M. I. CARSTENS AND E. CARSTENS *

University of California, Davis, Department of Neurobiology, Physiology & Behavior, 1 Shields Avenue, Davis, CA 95616, USA

1-s2.0-S0306452214001018-main

Abstract—We have further developed a behavioral model of itch and pain in the lower hindlimb (calf) originally reported by LaMotte et al. (2011) that allows comparisons with responses of lumbar dorsal horn neurons to pruritic and noxious stimuli. Intradermal (id) microinjection of the prurit- ogens histamine, SLIGRL-NH2 (agonist of PAR-2 and MrgprC11) and chloroquine (agonist of MrgprA3) into the calf of the lower limb elicited significant biting and a small amount of licking directed to the injection site, over a 30- min time course. Following id injection of histamine, low-threshold mechanical stimuli reliably elicited discrete episodes of biting (alloknesis) over a longer time course; significantly less alloknesis was observed following id injec- tion of SLIGRL-NH2. Capsaicin injections elicited licking but little biting. Following id injection of capsaicin, low-thresh- old mechanical stimuli elicited discrete hindlimb flinches (allodynia) over a prolonged (>2 h) time course. In single- unit recordings from superficial lumbar dorsal horn neurons, low-threshold mechanically evoked responses were significantly enhanced, accompanied by receptive field expansion, following id injection of histamine in histamine- responsive neurons. This was not observed in histamine- insensitive neurons, or following id injection of saline or SLIGRL-NH2, regardless of whether the latter activated the neuron or not. These results suggest that itch-responsive neurons are selectively sensitized by histamine but not SLI- GRL-NH2 to account for alloknesis. The presently described ‘‘calf’’ model appears to distinguish between itch- and pain- related behavioral responses, and provides a basis to inves- tigate lumbar spinal neural mechanisms underlying itch, alloknesis, pain and allodynia. Ó 2014 Published by Elsevier Ltd. on behalf of IBRO.

Key words: itch, alloknesis, pain, allodynia, scratching, dor- sal horn neuron.

Journal Club 2014-04-04

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Structure of the TRPV1 ion channel determined by electron cryo-microscopy

Transient receptor potential (TRP) channels are sensors for a wide range of cellular and environmental signals, but elucidating how these channels respond to physical and chemical stimuli has been hampered by a lack of detailed structural information. Here we exploit advances in electron cryo-microscopy to determine the structure of a mammalian TRP channel, TRPV1, at 3.4 Å resolution, breaking the side-chain resolution barrier for membrane proteins without crystallization. Like voltage-gated channels, TRPV1 exhibits four-fold symmetry around a central ion pathway formed by transmembrane segments 5–6 (S5–S6) and the intervening pore loop, which is flanked by S1–S4 voltage-sensor-like domains. TRPV1 has a wide extracellular ‘mouth’ with a short selectivity filter. The conserved ‘TRP domain’ interacts with the S4–S5 linker, consistent with its contribution to allosteric modulation. Subunit organization is facilitated by interactions among cytoplasmic domains, including amino-terminal ankyrin repeats. These observations provide a structural blueprint for understanding unique aspects of TRP channel function.

Liao et al_2013_Structure of the TRPV1 ion channel determined by electron cryo-microscopy

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