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.
    Journal of Investigative Dermatology 09/2014; 135(2). DOI:10.1038/jid.2014.412 · 7.22 Impact Factor
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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.
    Experimental Dermatology 10/2014; 24(1). DOI:10.1111/exd.12568 · 3.76 Impact Factor
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    ABSTRACT: CD271 is the low-affinity neurotrophin (p75NTR) receptor that belongs to the TNF-receptor superfamily. Because in human epidermis CD271 is predominantly expressed in transit amplifying (TA) cells, we evaluated the role of this receptor in keratinocyte differentiation and in the transition from keratinocyte stem cells (KSC) to progeny. Calcium induced an up-regulation of CD271 in subconfluent keratinocytes, which was prevented by CD271 siRNA. Furthermore, CD271 overexpression provoked the switch of KSC to TA cells, while silencing CD271 induced TA cells to revert to a KSC phenotype, as shown by the expression of β1-integrin and by the increased clonogenic ability. CD271(+) keratinocytes sorted from freshly isolated TA cells expressed more survivin and K15 than CD271(-) cells, and displayed a higher proliferative capacity. Early differentiation markers and K15 were more expressed in skin equivalent generated from CD271(+) TA than from those derived from CD271(-) TA cells. By contrast, late differentiation markers were more expressed in skin equivalents from CD271(-) than in reconstructs from CD271(+) TA cells. Finally, skin equivalents originated from CD271(-) TA cells displayed a psoriatic phenotype. These results indicate that CD271 is critical for keratinocyte differentiation and regulates the transition from KSC to TA cells.Journal of Investigative Dermatology accepted article preview online, 20 October 2014. doi:10.1038/jid.2014.454.
    Journal of Investigative Dermatology 10/2014; 135(3). DOI:10.1038/jid.2014.454 · 7.22 Impact Factor
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