The TRPV3 mutation associated with the hairless phenotype in rodents is constitutively active

Abstract

SummaryTRPV3 is a non-selective cation channel activated by warm to hot temperatures. In rodents, TRPV3 is highly expressed in basal keratinocytes of skin and oral/nasal epithelia. TRPV3 knockout mice showed impaired responses to innocuous and noxious heat but otherwise normal appearance and reactions to many sensory modalities. However, point mutations of TRPV3 at Gly573 to Ser and Cys have recently been linked to autosomal dominant hairless phenotypes and spontaneous dermatitis in mice and rats, implicating an important role for TRPV3 in alopecia and skin diseases. Exactly how the mutations affect TRPV3 function was unexplained. Here we show that both G573S and G573C mutations of murine TRPV3 are constitutively active in heterologous systems. In HEK293 cells, expression of the TRPV3 mutants causes cell death. In Xenopus oocytes, the constitutively active mutant channel is irresponsive to thermal and chemical stimuli but it reduces the temperature threshold and enhances the responses to heat and TRPV3 agonists of the wild type channel when they are co-expressed. We conclude that the G573S and G573C substitutions render the TRPV3 channel spontaneously active under normal physiological conditions, which in turn alters ion homeostasis and membrane potentials of skin keratinocytes, leading to hair loss and dermatitis-like skin diseases.

Calcium Plays a Central Role in the Sensitization of TRPV3 Channel to Repetitive Stimulations

“…In addition, TRPV3 is highly expressed in skin keratinocytes and is activated by allergens and skin sensitizers (9), to which enhanced responses upon repeated challenges are common as well. The more recent finding that constitutively active TRPV3 mutations cause hair loss and dermatitis-like skin diseases further illustrates the importance of properly tuned TRPV3 function in the overall health of the skin tissue (11,12). Thus, understanding the mechanism of sensitization of TRPV3 to repetitive stimulations will likely shed light on how the first defense system of our body sorts and learns different substances, as well as temperature changes, in the environment and try to distinguish beneficial resources (nutritious food as well as warm and cozy temperatures) from harmful conditions.…”

“…The TRPV3 null mice showed some deficits in sensing hot temperatures in the innocuous and noxious range but no other obvious sensory impairment (10). On the other hand, constitutively active mutations of TRPV3 have been linked to hair loss and atopic dermatitis-like skin lesions in rodents (11,12).…”

“…The TRPV3 null mice showed some deficits in sensing hot temperatures in the innocuous and noxious range but no other obvious sensory impairment (10). On the other hand, constitutively active mutations of TRPV3 have been linked to hair loss and atopic dermatitis-like skin lesions in rodents (11,12).In addition to temperature, the thermosensitive TRP channels are activated by a large number of structurally unrelated chemical ligands from exogenous as well as endogenous sources (13). This polymodal nature has become a common feature of the TRP channel family, implicating that multiple mechanisms and external stimuli may be involved in the activation and regulation of these channels.…”

Defective channels lead to an impaired skin barrier

“…Furthermore, TRPV3-null mice also exhibit a 'wavy' hair phenotype (Cheng et al, 2010), similar to transforming growth factor-a (TGFa) and EGFRknockout mice (Luetteke et al, 1993;Mann et al, 1993), supporting the link with EGFR signalling. By contrast, Olmsted syndrome patients with activating TRPV3 mutations exhibit diffuse alopecia, and mice carrying gain-of-function TRPV3 mutations are hairless (Asakawa et al, 2006;Xiao et al, 2008). Moreover, activation of TRPV3 in human hair follicle culture causes inhibition of hair shaft elongation and apoptosis-driven catagen formation (Borbíró et al, 2011).…”

TRP Channels and Pruritus

“…In an experimentally induced dry skin pruritus model, the application of acetone-ether-water treatment resulted in less intense scratching behavior, associated with decreased sprouting of sensory fibers, in TRPV3 KO mice than in wild-type controls [296]. In good accordance with the itch-inhibitory effect of the deletion of TRPV3, a gain-of-function (Gly573Ser) mutation of the trpv3 gene resulted in a spontaneously developing itchy dermatitis and a closely related hairless phenotype both on mice and rats [297,298]. Keratinocytes from these animals showed a highly augmented Ca 2+ elevation in response to thermal stimulation and histological analysis of the skin revealed the inhibition of hair follicle growth [299].…”