Store-operated calcium channels in skin

Abstract

The skin is a complex organ that acts as a protective layer against the external environment. It protects the internal tissues from harmful agents, dehydration, ultraviolet radiation and physical injury as well as conferring thermoregulatory control, sensation, immunological surveillance and various biochemical functions. The diverse cell types that make up the skin include 1) keratinocytes, which form the bulk of the protective outer layer; 2) melanocytes, which protect the body from ultraviolet radiation by secreting the pigment melanin; and 3) cells that form the secretory appendages: eccrine and apocrine sweat glands, and the sebaceous gland. Emerging evidence suggests that store-operated Ca²⁺ entry (SOCE), whereby depletion of intracellular Ca²⁺ stores triggers Ca²⁺ influx across the plasma membrane, is central to the normal physiology of these cells and thus skin function. Numerous skin pathologies including dermatitis, anhidrotic ectodermal dysplasia, hyperhidrosis, hair loss and cancer are now linked to dysfunction in SOCE proteins. Principal amongst these are the stromal interaction molecules (STIMs) that sense Ca²⁺ depletion and Orai channels that mediate Ca²⁺ influx. In this review, the roles of STIM, Orai and other store-operated channels are discussed in the context of keratinocyte differentiation, melanogenesis, and eccrine sweat secretion. We explore not only STIM1-Orai1 as drivers of SOCE, but also independent actions of STIM, and emerging signal cascades stemming from their activities. Roles are discussed for the elusive transient receptor potential canonical channel (TRPC) complex in keratinocytes, Orai channels in Ca²⁺-cyclic AMP signal crosstalk in melanocytes, and Orai isoforms in eccrine sweat gland secretion.

Keywords: Orai channels; STIM; TRPC channels; eccrine sweat gland; keratinocytes; melanocytes; skin; store-operated calcium entry.

FIGURE 1

STIM1 and Orai1 drive keratinocyte and melanocyte functions in the epidermis. Keratinocytes and melanocytes are critical protective cells in the epidermal layer (A). Keratinocytes proliferate in the basal layer and differentiate in response to elevated extracellular [Ca²⁺]. This is driven by the Ca²⁺-sensing receptor (CaSR) (B), which activates Gα_12/13 and Gα_q/11 proteins. ER Ca²⁺ mobilisation triggers SOCE, and the resultant cytosolic Ca²⁺ signals contribute to AP1 activation and differentiation (B). Large currents carried by TRPC channels accompany the Orai channel Ca²⁺ influx, although the mechanism of TRPC channel activation in keratinocytes is not understood. Melanocytes protect the body from ultraviolet radiation by secreting melanin granules into the surrounding tissue. This is controlled by two key pathways (C), each triggered by paracrine hormones secreted from the surrounding cells (C). α-Melanocyte stimulating hormone (αMSH) and endothelin-1 (ET-1) stimulate melanocyte-inducing transcription factor (MITF)-driven melanogenesis via Gα_s and Gα_q/11 pathways, respectively. Both pathways prompt IP₃-mediated ER Ca²⁺ store depletion and SOCE. Store depletion resulting from αMSH activity causes direct activation of adenylyl cyclase (AC6) by STIM1, producing a positive feedback loop where cyclic AMP production drives either protein kinase A (PKA) or EPAC activation to further activate phospholipase C (PLC), Ca²⁺ store depletion and SOCE.

FIGURE 2

STIM1 and Orai1 are critical regulators of eccrine clear cell sweat secretion. Distinct from the apocrine sweat gland and the sebaceous gland which each associate with hair follicles (A), the eccrine sweat gland secretes dilute sweat directly onto the skin surface. It is responsible for salt and fluid secretion, through a two-phase merocrine secretory mechanism (B). Acinar cells in the secretory coil drive fluid secretion by actively transporting Cl⁻, with Na⁺ following across the tight junctions, and water osmotically. Myoepithelial cells provide structural support to the secretory cells, whilst upstream ductal cells modify the ionic composition of the hypertonic primary sweat, ready for release onto the skin surface. Clear cells are the key drivers of eccrine fluid secretion (C). In addition the transepithelial transport of Cl⁻ ions (via the basolateral Na⁺-K⁺-2Cl^- co-transporter, NKCC1, and Ca²⁺-activated Cl⁻ channels, TMEM16A and Best2), these cells move water from the plasma to the gland lumen via basolateral and apical aquaporin 5 (AQP5) channels in response to stimulation from the sympathetic nerve termini (via mAChR activation). Gα_q/11 proteins generate a biphasic cytosolic Ca²⁺ signal through sequential IP₃-mediated ER Ca²⁺ release and store depletion resulting in STIM1-mediated Orai1 activation and SOCE. Elevated cytosolic [Ca²⁺] activates apical Ca²⁺-activated Cl⁻ channels (CaCCs) and Cl⁻ efflux, resulting in osmotically-driven water efflux into the sweat gland lumen (C).