Emerging Role of Transient Receptor Potential Vanilloid 4 (TRPV4) Ion Channel in Acute and Chronic Itch

Abstract

Itch is a clinical problem that leaves many sufferers insufficiently treated, with over 20 million cases in the United States. This is due to incomplete understanding of its molecular, cellular, and cell-to-cell signaling mechanisms. Transient receptor potential (TRP) ion channels are involved in several sensory modalities including pain, vision, taste, olfaction, hearing, touch, and thermosensation, as well as itch. Relative to the extensive studies on TRPV1 and TRPA1 ion channels in itch modulation, TRPV4 has received relatively little research attention and its mechanisms have remained poorly understood until recently. TRPV4 is expressed in ganglion sensory neurons and a variety of skin cells. Growing evidence in the past few years strongly suggests that TRPV4 in these cells contributes to acute and chronic disease-associated itch. This review focuses on the current experimental evidence involving TRPV4 in itch under pathophysiological conditions and discusses its possible cellular and molecular mechanisms.

Keywords: TRPV4; itch; keratinocytes; pruritogen; sensory neurons.

Figure 1

Schematic diagram depicting the potential mechanism underlying cholestatic itch. Cholestatic liver disease is associated with significantly elevated systemic LPC, which directly activates TRPV4 expressed in skin keratinocytes. This in turn leads to extracellular release of miR-146a via MEK–ERK–Rab5a/Rab27a signaling pathways. miR-146a functions as a pruritogen by activating TRPV1-expressing pruriceptor sensory neurons that innervate the skin. Activation of TRPV1 by miR-146a induces the sensation of itch via central pathways.