Ann Dermatol.  2018 Jun;30(3):265-275. 10.5021/ad.2018.30.3.265.

Skin Barrier and Calcium

• Lee SE
• Lee SH

• KMID: 2419166
• DOI: http://doi.org/10.5021/ad.2018.30.3.265

Abstract

Epidermal barrier formation and the maintenance of barrier homeostasis are essential to protect us from the external environments and organisms. Moreover, impaired keratinocytes differentiation and dysfunctional skin barrier can be the primary causes or aggravating factors for many inflammatory skin diseases including atopic dermatitis and psoriasis. Therefore, understanding the regulation mechanisms of keratinocytes differentiation and skin barrier homeostasis is important to understand many skin diseases and establish an effective treatment strategy. Calcium ions (Ca²âº) and their concentration gradient in the epidermis are essential in regulating many skin functions, including keratinocyte differentiation, skin barrier formation, and permeability barrier homeostasis. Recent studies have suggested that the intracellular Ca²âº stores such as the endoplasmic reticulum (ER) are the major components that form the epidermal calcium gradient and the ER calcium homeostasis is crucial for regulating keratinocytes differentiation, intercellular junction formation, antimicrobial barrier, and permeability barrier homeostasis. Thus, both Ca²âº release from intracellular stores, such as the ER and Ca²âº influx mechanisms are important in skin barrier. In addition, growing evidences identified the functional existence and the role of many types of calcium channels which mediate calcium flux in keratinocytes. In this review, the origin of epidermal calcium gradient and their role in the formation and regulation of skin barrier are focused. We also focus on the role of ER calcium homeostasis in skin barrier. Furthermore, the distribution and role of epidermal calcium channels, including transient receptor potential channels, store-operated calcium entry channel Orai1, and voltage-gated calcium channels in skin barrier are discussed.

Keyword

Barrier; Calcium; Endoplasmic reticulum; Keratinocytes; Orai1; Transient receptor potential channels

MeSH Terms

Calcium Channels
Calcium*
Dermatitis, Atopic
Endoplasmic Reticulum
Epidermis
Homeostasis
Intercellular Junctions
Ions
Keratinocytes
Permeability
Psoriasis
Skin Diseases
Skin*
Transient Receptor Potential Channels
Calcium
Calcium Channels
Ions
Transient Receptor Potential Channels

Figure

• 

  Fig. 1 Proposed role of endoplasmic reticulum (ER) calcium signaling in the permeability barrier homeostasis. Recent studies suggested that the intracellular calcium store such as the ER is the major compartment which forms the epidermal calcium gradient. Permeability barrier disruption stimulates Ca2+ release from ER in keratinocytes of stratum granulosum (SG), causing ER Ca2+ depletion and the loss of epidermal calcium gradient. ER Ca2+ depletion stimulates lamellar bodies (LBs) secretion and the expression of caspase 14 and loricrin, indicating that ER Ca2+ change is a critical signal for initiating the two key metabolic responses (lipid and protein barrier restoration) that lead to barrier recovery. The next physiological response to ER Ca2+ depletion is a rapid increase in store-operated Ca2+ entry, a mechanism involved in refilling of ER Ca2+ stores. Stromal interaction molecule 1 (STIM1) is an ER Ca2+ sensor that triggers the store-operated Ca2+ entry. In the SG, this store-operated Ca2+ entry is mediated by TRPC1 and TRPC4. This calcium influx through TRPC1 and TRPC4 further stimulates keratinocyte differentiation. SERCA: sarco/endoplasmic reticulum Ca2+-ATPase isoform.

• 

  Fig. 2 The role of various calcium channels in skin barrier homeostasis and itch. Epidermal keratinocytes functionally express many calcium channels including transient receptor potential (TRP) channels and the components of the store-operated calcium entry (SOCE) pathway such as Ca2+ influx channel Orai1. TRPV6 expression is upregulated in the differentiated keratinocytes, where TRPV6 is implicated in the formation of epidermal calcium gradient and differentiation. TRPC channels in skin play a role in store-operated channels (SOC)-related Ca2+ entry pathways. TRPC1, TRPC4, and TRPC6 play a role in differentiation. In addition to TRPC channels, important player of SOC in skin is Orai1, which is mainly expressed in basal cell layer. Orai1 plays important roles in cellular proliferation, migration, and itch signals. TRPV3 and TRPV4 are activated by warm temperatures. TRPV3 plays a role in skin barrier formation and differentiation in keratinocyte through a transforming growth factor-alpha/epidermal growth factor receptor–complex, however, overactive TRPV3 stimulates abnormal keratinocytes proliferation. TRPV4 plays a role in the formation of epidermal tight junction (TJ). TRPV3 and TRPV4, which are strongly expressed in keratinocytes, have been implicated in itch, possibly by releasing various mediators to stimuli the sensory nerves. The heat-sensitive channel TRPV1 delays barrier recovery, in contrast the cold-sensitive channels TRPA1 and TRPM8 accelerate barrier recovery. TSLP: thymic stromal lymphopoietin.

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