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ENaC and its positive regulator, the channel activating protease 1 (CAP1): molecular and functional characterization in epidermal remodeling, differentiation and physiology

English title ENaC and its positive regulator, the channel activating protease 1 (CAP1): molecular and functional characterization in epidermal remodeling, differentiation and physiology
Applicant Hummler Edith
Number 102125
Funding scheme Project funding
Research institution Département de Pharmacologie & Toxicologie Faculté de Biologie et de Médecine Université de Lausanne
Institution of higher education University of Lausanne - LA
Main discipline Physiology : other topics
Start/End 01.10.2003 - 30.09.2006
Approved amount 202'938.00
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Keywords (6)

amiloride-sensitive epithelial sodium channel (ENa; sodium channel (ENaC); channel activating protease (CAP); sodium transport; skin; conditional gene targeting

Lay Summary (English)

Lead
Lay summary
In mammalian skin, the epithelial sodium channel (ENaC) is expressed in epidermis and hair follicles and the expression of ENaC subunits is enhanced as keratinocytes differentiate. Using gene targeting strategy, we generated classical and conditional knockout mice of ENaC and one of its regulators, the channel-activating protease 1 (CAP1) to study their implication in skin under physiological and pathophysiological conditions.Detailed analysis of alpha-ENaC-deficient mice revealed that ENaC expression is required for normal epidermal differentiation suggesting a novel role of ENaC in skin. Alpha-ENaC activity controls selective aspects of epidermal differentiation, including synthesis of markers of differentiation, keratohyalin granule formation, and lipid secretion. As a physiological consequence, alpha-ENaC knockout mice show after birth a severe transepidermal water loss and loose significant more weight, most likely due to impairment of the barrier function. They exhibit an impaired skin surface acidification accompanied by significant changes in lipid processing and/or maturation. The disturbed synthesis of lipids is characteristic for a model of impaired barrier function and seems to be a common feature of reduced ENaC activity in skin. This phenotype resembles features of psoriasis or psoriasiform dermatoses in human further indicating that ENaC might be implicated in ichthyoses.Serine proteases are proteolytic enzymes involved in regulation of various physiological processes. By generating mice lacking the membrane-anchored channel activating serine protease 1 (CAP1; also termed Prss8, prostasin) in skin, we found that knockout mice die within 60 hours after birth. They present a lower body weight and exhibit severe malformation of the stratum corneum. This aberrant skin development is accompanied by an impaired skin barrier function as evidenced by dehydration and skin permeability assay, and transepidermal water loss measurements leading to rapid, fatal dehydration. Analysis of differentiation markers revealed no major alterations in CAP1/Prss8-deficient skin, even though epidermal deficiency of CAP1/Prss8 expression disturbs the stratum corneum lipid composition, the corneocyte morphogenesis and processing of profilaggrin. Further examination revealed absence of the tight junction protein occludin which did not prevent diffusion of subcutaneously injected tracer toward the skin surface. Such tight junction proteins might thus be novel targets of this membrane-bound serine protease. In conclusion, CAP1/Prss8 expression in the epidermis is crucial for the epidermal permeability barrier, thereby being indispensable for postnatal survival.Altogether, ENaC and its positive regulator, CAP1/Prss8 are both implicated in the epidermal barrier function and are the first members of the group of genes required rather for maintenance than for generation of the epidermal permeability barrier function after birth.
Direct link to Lay Summary Last update: 21.02.2013

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Associated projects

Number Title Start Funding scheme
63801 Molecular physiology of ENaC-mediated sodium transport in skin and lung epithelium 01.04.2001 Project funding
113422 Physiological and pathophysiological role of CAP1 and ENaC in the epidermal permeability barrier function 01.10.2006 Project funding

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