ORAI1 calcium channel orchestrates skin homeostasis

Abstract

To achieve and maintain skin architecture and homeostasis, keratinocytes must intricately balance growth, differentiation, and polarized motility known to be governed by calcium. Orai1 is a pore subunit of a store-operated Ca 2+ channel that is a major molecular counterpart for Ca 2+ influx in nonexcitable cells. To elucidate the physiological significance of Orai1 in skin, we studied its functions in epidermis of mice, with targeted disruption of the orai1 gene, human skin sections, and primary keratinocytes. We demonstrate that Orai1 protein is mainly confined to the basal layer of epidermis where it plays a critical role to control keratinocyte proliferation and polarized motility. Orai1 loss of function alters keratinocyte differentiation both in vitro and in vivo. Exploring underlying mechanisms, we show that the activation of Orai1-mediated calcium entry leads to enhancing focal adhesion turnover via a PKCβ-Calpain-focal adhesion kinase pathway. Our findings provide insight into the functions of the Orai1 channel in the maintenance of skin homeostasis.calcium signaling | cell migration | orai1 KO mice

Endoplasmic Reticulum Calcium Regulates Epidermal Barrier Response and Desmosomal Structure

“…Defective ER calcium homeostasis causes desmosomal abnormalities and acantholysis in Darier disease. Recently, ER calcium signaling in keratinocytes has been linked to regulation of desmosomal adhesion through protein kinase C activation (Hobbs et al, 2011), focal adhesion turnover, cell migration, and differentiation through ORAI1-dependent store operated calcium entry (Vandenberghe et al, 2013), itch in an atopic dermatitis model through peroxisome proliferator-activated receptor 2 activation, and thymic stromal lymphopoietin release (Baek et al, 2013). …”

Spontaneous calcium transients manifest in the regenerating muscle and are necessary for skeletal muscle replenishment

“…This could be due to the dependence on Ca 2+ dynamics for the proliferation of cell precursors of all regenerating tissues in the tail. Indeed, skin repair after wound healing in Xenopus embryos and skin homeostasis in human cells and mice depend on Ca 2+ stores for the enhancement of skin cell proliferation [37, 38]. Similarly, neural cell precursor proliferation is regulated by Ca 2+ dynamics [21, 35, 36].…”

Alternative splicing converts STIM2 from an activator to an inhibitor of store-operated calcium channels

“…The most well-characterized store-operated channel is the Ca 2+ release-activated Ca 2+ (CRAC) channel, and defects in its function cause severe combined immunodeficiency (Feske et al, 2006(Feske et al, , 2010 as well as deficits in muscle development and function (Stiber et al, 2008;Darbellay et al, 2010;Wei-LaPierre et al, 2013), platelet function (Varga-Szabo et al, 2011), and skin homeostasis (Vandenberghe et al, 2013).…”