Involvement of skin TRPV3 in temperature detection regulated by TMEM79 in mice

Abstract

TRPV3, a non-selective cation transient receptor potential (TRP) ion channel, is activated by warm temperatures. It is predominantly expressed in skin keratinocytes, and participates in various somatic processes. Previous studies have reported that thermosensation in mice lacking TRPV3 was impaired. Here, we identified a transmembrane protein, TMEM79, that acts as a negative regulator of TRPV3. Heterologous expression of TMEM79 was capable of suppressing TRPV3-mediated currents in HEK293T cells. In addition, TMEM79 modulated TRPV3 translocalization and promoted its degradation in the lysosomes. TRPV3-mediated currents and Ca2+ influx were potentiated in primary mouse keratinocytes lacking TMEM79. Furthermore, TMEM79-deficient male mice preferred a higher temperature than did wild-type mice due to elevated TRPV3 function. Our study revealed unique interactions between TRPV3 and TMEM79, both in vitro and in vivo. These findings support roles for TMEM79 and TRPV3 in thermosensation.

Unlocking the therapeutic potential of TRPV3: Insights into thermosensation, channel modulation, and skin homeostasis involving TRPV3

“…Our recent study further highlights a role for TRPV3 in skin pathophysiology. [ 5 ] As mentioned above, we reported that TMEM79 negatively regulates TRPV3 function in skin keratinocytes and concluded that TRPV3 indeed contributes to temperature sensing in mice. TMEM79 is a membrane protein with five transmembrane domains that is reported to be involved in skin barrier function.…”

“…We recently used a Thermal Gradient Ring (TGR) having a narrower temperature range (10°C–45°C) to confirm that TRPV3 is indeed involved in warmth sensation by showing the indifference of mice to innocuous temperature. [ 5 ] In addition, we showed that TMEM79‐knockout mice prefer to stay at a bit higher optimal temperature than wild‐type mice likely due to increased TRPV3 levels on the plasma membrane, thus supporting a role for skin TRPV3 in thermosensation. [ 5 ] A recent commentary article raised several critical questions for future directions of TRPV3 warmth sensation research.…”

“…[ 5 ] In addition, we showed that TMEM79‐knockout mice prefer to stay at a bit higher optimal temperature than wild‐type mice likely due to increased TRPV3 levels on the plasma membrane, thus supporting a role for skin TRPV3 in thermosensation. [ 5 ] A recent commentary article raised several critical questions for future directions of TRPV3 warmth sensation research. [ 76 ] For example, keratinocyte‐specific conditional TMEM79‐knockout mice are required in the future to overcome the contribution of other cell types in the elevated optimum temperature response.…”

“…Importantly, our recent study revealed that TMEM79, a membrane protein that is enriched in keratinocytes, decreased TRPV3 expression in the cell membrane through lysosome‐dependent degradation (Figure 3). [ 5 ] This finding highlighted the significance of TMEM79 in modulating physiological functions in skin that involve TRPV3. As such, the study of the cellular mechanisms involved in TRPV3 translocation and/or mobilization in keratinocytes will contribute to a better understanding of the role of TRPV3 membrane density in skin physiology.…”

“…Although earlier studies on the contribution of TRPV3 to warmth sensation had varying results depending on the specific experimental conditions and models, recent research confirmed the involvement of TRPV3 in sensing warm temperature. [ 5 ] In this review, we discuss previous research concerning TRPV3, and explore both its molecular mechanisms and functional significance in skin homeostasis. By elucidating regulatory pathways for TRPV3, this review aims to provide a comprehensive understanding of the physiological significance of this channel and its implications in skin biology and disease.…”