Tu CL, Bikle DD.Role of the calcium-sensing receptor in calcium regulation of epidermal differentiation and function. Best Pract Res Clin Endocrinol Metab 27:415-427

Endocrine Unit, Veterans Affair Medical Center and The University of California, San Francisco, CA, USA.
Best practice & research. Clinical endocrinology & metabolism 06/2013; 27(3):415-27. DOI: 10.1016/j.beem.2013.03.002
Source: PubMed


The epidermis is a stratified squamous epithelium composed of proliferating basal and differentiated suprabasal keratinocytes. It serves as the body's major physical and chemical barrier against infection and harsh environmental insults, as well as preventing excess water loss from the body into the atmosphere. Calcium is a key regulator of the proliferation and differentiation in keratinocytes. Elevated extracellular Ca(2+) concentration ([Ca(2+)]o) raises the levels of intracellular free calcium ([Ca(2+)]i), promotes cell-cell adhesion, and activates differentiation-related genes. Keratinocytes deficient in the calcium-sensing receptor fail to respond to [Ca(2+)]o stimulation and to differentiate, indicating a role for the calcium-sensing receptor in transducing the [Ca(2+)]o signal during differentiation. The concepts derived from in vitro gene knockdown experiments have been evaluated and confirmed in three mouse models in vivo.

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    • "Although there have been many studies performed to elucidate the regulation of these proliferation and differentiation processes, the exact regulators and signaling mechanism(s) underlying these events are still unclear. One of the well-known regulators of epidermal differentiation is the extracellular calcium concentration , with lower concentrations maintaining a proliferative state and elevated levels inducing differentiation (Tu and Bikle, 2013). Aquaporins are a family of transmembrane proteins that facilitate the transport of water, and in some cases small solutes, across cell membranes (Verkman, 2008). "
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    ABSTRACT: Aquaporin-3 (AQP3) is a water and glycerol channel expressed in epidermal keratinocytes. Despite many studies, controversy remains about the role of AQP3 in keratinocyte differentiation. Previously, our laboratory has shown co-localization of AQP3 and phospholipase D2 (PLD2) in caveolin-rich membrane microdomains. We hypothesized that AQP3 transports glycerol and “funnels” this primary alcohol to PLD2 to form a pro-differentiative signal, such that the action of AQP3 to induce differentiation should require PLD2. To test this idea, we re-expressed AQP3 in mouse keratinocytes derived from AQP3-knockout mice. The re-expression of AQP3, which increased [3H]glycerol uptake, also induced mRNA and protein expression of epidermal differentiation markers such as keratin 1, keratin 10 and loricrin, with or without the induction of differentiation by an elevated extracellular calcium concentration. Re-expression of AQP3 had no effect on the expression of the proliferation markers keratin 5 and cyclin D1. Furthermore, a selective inhibitor of PLD2, CAY10594, and a lipase-dead PLD2 mutant, but not a lipase-dead PLD1 mutant, significantly inhibited AQP3 re-expression-induced differentiation marker expression with calcium elevation, suggesting a role for PLD2 in this process. Thus, our results indicate that AQP3 has a pro-differentiative role in epidermal keratinocytes and that PLD2 activity is necessary for this effect.
    Full-text · Article · Sep 2014 · Journal of Investigative Dermatology
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    ABSTRACT: The human epidermis provides a very effective barrier function against chemical, physical and microbial insults from the environment. This is only possible as the epidermis renews itself constantly. Stem cells located at the basal lamina which forms the dermoepidermal junction provide an almost inexhaustible source of keratinocytes which differentiate and die during their journey to the surface where they are shed off as scales. Despite the continuous renewal of the epidermis it nevertheless succumbs to aging as the turnover rate of the keratinocytes is slowing down dramatically. Aging is associated with such hallmarks as thinning of the epidermis, elastosis, loss of melanocytes associated with an increased paleness and lucency of the skin and a decreased barrier function. As the differentiation of keratinocytes is strictly calcium dependent, calcium also plays an important role in the aging epidermis. Just recently it was shown that the epidermal calcium gradient in the skin that facilitates the proliferation of keratinocytes in the stratum basale and enables differentiation in the stratum granulosum is lost in the process of skin aging. In the course of this review we try to explain how this calcium gradient is built up on the one hand and is lost during aging on the other hand. It will also be discussed how this disturbed calcium homeostasis is affecting the gene expression in aged skin and is leading to dramatic changes in the composition of the cornified envelope. This loss of the epidermal calcium gradient is not specific for skin aging but can also be found in skin diseases such as Darier disease, Hailey-Hailey disease, psoriasis and atopic dermatitis, which might be very helpful to get a deeper insight in skin aging.
    No preview · Article · Sep 2014 · Experimental Gerontology
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    ABSTRACT: Calcium-mediated signals play important roles in epidermal barrier formation, skin homeostasis, and wound repair. Calmodulin 4 (Calm4) is a small, Ca(2+) binding protein with strong expression in suprabasal keratinocytes. In mice, Calm4 first appears in the skin at the time of barrier formation and its expression increases in response to epidermal barrier challenges. In this study, we report the generation of Calm4 knockout mice and provide evidence that Calm4 is dispensable for epidermal barrier formation, maintenance, and repair. This article is protected by copyright. All rights reserved.
    No preview · Article · Oct 2014 · Experimental Dermatology
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