Trp channels and itch

Abstract

Itch is a unique sensation associated with the scratch reflex. Although the scratch reflex plays a protective role in daily life by removing irritants, chronic itch remains a clinical challenge. Despite urgent clinical need, itch has received relatively little research attention and its mechanisms have remained poorly understood until recently. The goal of the present review is to summarize our current understanding of the mechanisms of acute as well as chronic itch and classifications of the primary itch populations in relationship to transient receptor potential (Trp) channels, which play pivotal roles in multiple somatosensations. The convergent involvement of Trp channels in diverse itch signaling pathways suggests that Trp channels may serve as promising targets for chronic itch treatments.

Sensory Neurons Co-opt Classical Immune Signaling Pathways to Mediate Chronic Itch

“…Thus, we predict that alterations in classical STAT-mediated transcriptional changes alone are insufficient to explain how IL-4Rα modulates sensory neurons. Previous studies have shown that TRP channels harbor several phosphorylation sites and can be regulated by multiple kinases (Sun and Dong, 2016; Zheng, 2013). Although JAKs typically phosphorylate STAT proteins within immune cells, our current study provokes the hypothesis that JAK proteins may have novel functions in neurons and may regulate TRP channels by unknown pathways.…”

β-arrestin-1: Bridging GPCRs to active TRP channels

“…The activation of TRP channels by GPCRs has been reported previously, but they are mainly dependent on G protein signal pathways, leading to changes in the membrane expression and/or activation threshold of TRP channels. [1][2][3]5,7 The finding that AT1R-b-arrestin-1 specifically activates TRPC3 is interesting and totally different from the canonical Gq-PLCb pathway that often shows a nonselective modulation of several distinct TRP channels. 1,2 Since b-arrestin-1 may mediate coupling of AT1R and TRPC3 by a direct functional complex formation or through an indirect cascade signaling pathway, Liu et al 5 thus performed co-immunoprecipitations, bioluminescence resonance energy transfer experiments, and patch clamp recordings.…”

“…TRP channels are a superfamily of Ca 2C -permeable cation nonselective channels that play critical roles in various sensory functions, such as thermosensation, mechanosensation, pain, itch, and chronic inflammatory sensation. 2,7 TRP channels cannot only be directly activated by various chemical, mechanical and thermal stimuli, but also function as major effectors of GPCRs downstream of G protein-dependent signal transduction pathways. [1][2][3]8 In this highlighted study, Liu and colleagues 5 unexpectedly identified a new b-arrestin-1-mediated, G protein-independent, fast communication between GPCR and TRPC3, which substantially contributes to acute catecholamine secretion following AT1R activation.…”

“…2,7 TRP channels cannot only be directly activated by various chemical, mechanical and thermal stimuli, but also function as major effectors of GPCRs downstream of G protein-dependent signal transduction pathways. [1][2][3]8 In this highlighted study, Liu and colleagues 5 unexpectedly identified a new b-arrestin-1-mediated, G protein-independent, fast communication between GPCR and TRPC3, which substantially contributes to acute catecholamine secretion following AT1R activation. 5 With the specific G protein or b-arrestin-1 biased AT1R agonists and knockout mice models, Liu et al 5 found that not only the Gq-PLCb-mediated pathway but also b-arrestin-1-biased agonism are capable of stimulating acute catecholamine secretion from adrenal chromaffin cells.…”

“…[1][2][3] GPCRs are ubiquitiously expressed 7-transmembrane receptors that fine-tune cellular functions by activating a heterotrimeric G protein-dependent cascade of acute (in seconds) and long-term signals (e.g., G q -PLCb-DAG-PKC and G s -AC-cAMP-PKA signaling pathways). 1,4 In addition to activating G proteins, GPCRs also transduce extracellular signals by activating arrestinmediated cell responses, such as hydrolysis of cAMP or kinase cascade signals known as the second wave of GPCR signaling (> 2-3 minutes).…”