| First Author | Wang Y | Year | 2021 |
| Journal | Cell Biol Toxicol | Volume | 37 |
| Issue | 2 | Pages | 313-330 |
| PubMed ID | 32535744 | Mgi Jnum | J:304414 |
| Mgi Id | MGI:6694997 | Doi | 10.1007/s10565-020-09536-2 |
| Citation | Wang Y, et al. (2021) TRPV3 enhances skin keratinocyte proliferation through EGFR-dependent signaling pathways. Cell Biol Toxicol 37(2):313-330 |
| abstractText | Transient receptor potential vanilloid 3 (TRPV3) is highly expressed in skin keratinocytes where it forms Ca(2+)-permeable nonselective cation channels to regulate various cutaneous functions. TRPV3 expression is upregulated in many skin disorders. Here, we examined how TRPV3 affects keratinocyte proliferation and investigated the underlying mechanism. Topical application of TRPV3 agonist, carvacrol, increased skin thickness in wild type (WT) mice but not in TRPV3 knockout (KO) mice. Carvacrol promoted proliferation of human keratinocytes HaCaT cells at concentrations </= 100 muM, but at 300 muM, it decreased cell viability, suggesting a nonmonotonic proliferative effect. Suppression of TRPV3 expression abolished carvacrol-induced cell proliferation while overexpression of TRPV3 enhanced HaCaT cell proliferation. Carvacrol also stimulated Ca(2+) influx and proliferation of primary keratinocytes prepared from WT but not TRPV3 KO mice, suggesting that carvacrol-stimulated cell proliferation was dependent on TRPV3-mediated Ca(2+) influx. Mechanistic investigation demonstrated that carvacrol stimulated TGFalpha release and increased phosphorylation levels of EGFR, PI3K, and NF-kappaB, effects abolished by suppression of TRPV3 expression and CaMKII inhibition. Moreover, inhibition of CaMKII, EGFR, PI3K, or NF-kappaB diminished carvacrol-induced cell proliferation. We conclude that while strong activation of TRPV3 may cause cell death, moderate activation of TRPV3 promotes cell proliferation in keratinocytes through Ca(2+)/CaMKII-->TGFalpha/EGFR-->PI3K-->NF-kappaB signaling. Graphical abstract Headlights 1. Carvacrol induces epidermal hyperplasia and keratinocyte proliferation. 2. TRPV3 mediates carvacrol-induced epidermal hyperplasia and keratinocyte proliferation. 3. TRPV3 acts through Ca(2+)/CaMKII-->TGFalpha/EGFR-->PI3K-->NF-kappaB signaling to promote keratinocyte proliferation. |
