Abstract
Temperature-sensitive and calcium-permeable transient receptor potential vanilloid 3 (TRPV3) channel abundantly expressed in the keratinocyte plays important functions in the skin physiology. Dysfunctional gain-of-function mutations of TRPV3 cause genetic Olmsted Syndrome (OS) characterized by palmoplantar and periorificial keratoderma, inflammation and severe itch, suggesting that pharmacological inhibition of overactive TRPV3 may be beneficial for therapy of pruritus or skin disorders. To test this hypothesis, we identified a natural compound forsythoside B as an inhibitor of TRPV3 through a screen of HEK293 cells expressing human TRPV3 channels in calcium fluorescent assay. Whole-cell patch clamp recordings further confirmed that forsythoside B selectively inhibited TRPV3 current activated by TRP channel agonist 2-APB (50-->µ<--M) in dose-dependent manner with an IC50 value of 6.7-->± <--0.7 µM. In vivo evaluation of scratching behavior demonstrates that inhibition of TRPV3 by forsythoside B significantly attenuated acute itch induced by either TRPV3 agonist carvacrol or pruritogen histamine, and also chronic itch of dry skin induced by acetone-ether-water (AEW) in mice. Furthermore, forsythoside B is able to prevent cell death of HEK293 cells and native HaCaT cells from human keratinocytes expressing gain-of-function TRPV3 G573S mutant or in the presence of TRPV3 agonist carvacrol. Taken together, our findings demonstrate the crucial role of TRPV3 in pruritus and keratinocyte toxicity, and specific inhibition of overactive TRPV3 by natural forsythoside B may possess therapeutic potential for chronic pruritus, skin allergy or inflammation-related skin diseases.
- The American Society for Pharmacology and Experimental Therapeutics