A STUDY OF PAIN AND ITCH: AN INVESTIGATION OF PIRT2, TRPS, AND MRGPRS IN THE PERIPHERAL NERVOUS SYSTEM
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Date
2013-12-11
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Johns Hopkins University
Abstract
Both pain and itch are important sensory modalities for the survival of organisms. Here we aim at understanding the natures of these two senses. In the first chapter, we have identified a novel protein Pirt2 as a potentiating modulator for TRPA1-V1 complex. In the dorsal root ganglia (DRG) Pirt2 is expressed in the majority of peptidergic neurons, where TRPA1 and TRPV1 are highly enriched. Mice deficient in Pirt2 on sensory neurons showed selectively impaired TRPA1-associated but intact TRPV1-associated nociceptive behaviors. Single channel recordings in the heterologous system revealed that Pirt2 selectively potentiated TRPA1 activities in the TRPA1-V1 complex and the modulation was TRPV1-dependent. Mechanistically, Pirt2 disrupts the physical association of TRPA1-V1 and releases the inhibition by TRPV1 on TRPA1. Our study demonstrated Pirt2 as a modulator for TRPA1-V1 complex and a novel drugable target for pain treatment.
In the following chapter, we showed that Mrgprs (Mas-related G protein–coupled receptors, a.k.a. MRG), particularly MrgprC11, rather than PAR2 (protease-activated receptor 2), mediated histamine-independent itch. A shorter peptide, SLIGR, which specifically activated PAR2 but not MrgprC11, induced thermal pain hypersensitivity in mice but not a scratch response. Therefore, although both MrgprC11 and PAR2 are SLIGRL-responsive G protein–coupled receptors in DRG, each plays a specific role in mediating itch and pain. Overall, our studies provided the evidence to better understand the nature of itch and pain at the peripheral level.
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Pain, Itch