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Intracellular Ca(2+) signaling via various calcium channels, such as Orai1, Transient receptor potential (TRP)A1 and TRPV3, has been shown to directly modulate epidermal proliferation, differentiation, barrier homeostasis, and inflammation. Ca(2+) influx through these channels eventually generates intracellular Ca(2+) signaling that results in different outcomes dependent on the individual Ca(2+) channel type, for example, keratinocyte proliferation and migration through Orai1, epidermal barrier formation and keratinocyte differentiation through TRPA1, and keratinocyte cornification through TRPV3. Therefore, a specific agonist/antagonist for each calcium channel is required for maintaining skin barrier homeostasis and for the treatment of dermatological diseases. To identify applicable topical botanically derived chemicals for use in functional cosmetics or agents for dermatological diseases. Novel modulators of Orai1, TRPA1 and TRPV3 were identified were identified by screening the extracts (plus their fractions) of 30 medicinal herbs and their constituents. The potencies of the activating and inhibitory compounds of each channel were determined by an automated patch clamp system. The biophysical properties of channel modulation by hit products were re-analyzed using conventional whole-cell patch clamp and fluorometric calcium imaging. We prepared the extracts of 30 medicinal herbs, performed bioassay-guided fractionation of the active extracts, and then isolated and identified the bioactive constituents. By performing the combination of automated and conventional whole-cell patch clamp studies, we found eight medicinal herb fractions for Orai1, two for TRPA1, and three for TRPV3 that showed >50% inhibition rates at 30 μg/mL. We also found three fractions with TRPA1 agonist activity. Chemical constituents that showed agonist/antagonistic effects also will be discussed. Considering that most regional plants have not been investigated chemically or pharmaceutically, they remain as untapped potential sources of topical agents for cosmetics and drugs. We found major active components and chemical constituents of plant extracts for the modulation of various calcium ion channels, which may have potential clinical applications for abnormal skin barrier functions such as atopic dermatitis, elastosis, and contact dermatitis and so on. Extensive clinical studies of the lead compounds are needed to develop topical agents for dermatological diseases that relate to skin barrier functions.
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