The human transient receptor potential vanilloid 3 channel is sensitized via the ERK pathway

0485941 - FGÚ 2018 RIV US eng J - Journal Article
Vyklická, Lenka - Boukalová, Štěpána - Máčiková, Lucie - Chvojka, Štěpán - Vlachová, Viktorie
The human transient receptor potential vanilloid 3 channel is sensitized via the ERK pathway.
Journal of Biological Chemistry. Roč. 292, č. 51 (2017), s. 21083-21091. ISSN 0021-9258. E-ISSN 1083-351X
R&D Projects: GA ČR(CZ) GA15-15839S
Institutional support: RVO:67985823
Keywords : epidermal growth factor receptor (EGFR) * extracellular-signal-regulated kinase (ERK) * keratinocyte * phosphorylation * transient receptor potential channels * TRP channels
OECD category: Neurosciences (including psychophysiology
Impact factor: 4.011, year: 2017

The transient receptor potential vanilloid 3 (TRPV3) channel is a Ca2+-permeable thermosensitive ion channel widely expressed in keratinocytes, where together with epidermal growth factor receptor (EGFR) forms a signaling complex regulating epidermal homeostasis. Proper signaling through this complex is achieved and maintained via several pathways in which TRPV3 activation is absolutely required. Results of recent studies have suggested that low-level constitutive activity of TRPV3 induces EGFR-dependent signaling that, in turn, amplifies TRPV3 via activation of the mitogen-activated protein kinase ERK in a positive feedback loop. Here, we explored the molecular mechanism that increases TRPV3 activity through EGFR activation. We used mutagenesis and whole-cell patch clamp experiments on TRPV3 channels endogenously expressed in an immortalized human keratinocyte cell line (HaCaT) and in transiently transfected HEK293T cells and found that the sensitizing effect of EGFR on TRPV3 is mediated by ERK. We observed that ERK-mediated phosphorylation of TRPV3 alters its responsiveness to repeated chemical stimuli. Among several putative ERK phosphorylation sites, we identified threonine 264 in the N-terminal ankyrin repeat domain as the most critical site for the ERK-dependent modulation of TRPV3 channel activity. Of note, Thr264 is in close vicinity to a structurally and functionally important TRPV3 region comprising an atypical finger 3 and oxygen-dependent hydroxylation site. In summary, our findings indicate that Thr264 in TRPV3 is a key ERK phosphorylation site mediating EGFR-induced sensitization of the channel to stimulate signaling pathways involved in regulating skin homeostasis.
Permanent Link: http://hdl.handle.net/11104/0280858