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Sensitization of small-diameter sensory neurons is controlled by TRPV1 and TRPA1 association.

Research paper by Mayur J MJ Patil, Margaux M Salas, Siarhei S Bialuhin, Jacob T JT Boyd, Nathaniel A NA Jeske, Armen N AN Akopian

Indexed on: 11 Jan '20Published on: 10 Jan '20Published in: FASEB journal : official publication of the Federation of American Societies for Experimental Biology



Abstract

Unique features of sensory neuron subtypes are manifest by their distinct physiological and pathophysiological functions. Using patch-clamp electrophysiology, Ca imaging, calcitonin gene-related peptide release assay from tissues, protein biochemistry approaches, and behavioral physiology on pain models, this study demonstrates the diversity of sensory neuron pathophysiology is due in part to subtype-dependent sensitization of TRPV1 and TRPA1. Differential sensitization is influenced by distinct expression of inflammatory mediators, such as prostaglandin E (PGE), bradykinin (BK), and nerve growth factor (NGF) as well as multiple kinases, including protein kinase A (PKA) and C (PKC). However, the co-expression and interaction of TRPA1 with TRPV1 proved to be the most critical for differential sensitization of sensory neurons. We identified N- and C-terminal domains on TRPV1 responsible for TRPA1-TRPV1 (A1-V1) complex formation. Ablation of A1-V1 complex with dominant-negative peptides against these domains substantially reduced the sensitization of TRPA1, as well as BK- and CFA-induced hypersensitivity. These data indicate that often occurring TRP channel complexes regulate diversity in neuronal sensitization and may provide a therapeutic target for many neuroinflammatory pain conditions. © 2019 Federation of American Societies for Experimental Biology.