Calcium Channels: Noteworthy Regulators and Therapeutic Targets in Dermatological Diseases

Abstract

Dysfunctional skin barrier and impaired skin homeostasis may lead to or aggravate a series of dermatologic diseases. A large variety of biological events and bioactive molecules are involved in the process of skin wound healing and functional recovery. Calcium ions (Ca2+) released from intracellular stores as well as influx through plasma membrane are essential to skin function. Growing evidence suggests that calcium influx is mainly regulated by calcium-sensing receptors and channels, including voltage-gated, transient potential receptor, store-operated, and receptor-operated calcium channels, which not only maintain cellular Ca2+ homeostasis, but also participate in cell proliferation and skin cell homeostasis through Ca2+-sensitive proteins such as calmodulin (CaM). Furthermore, distinct types of Ca2+ channels not merely work separately, they may work concertedly to regulate cell function. In this review, we discussed different calcium-sensing receptors and channels, including voltage-gated, transient receptor potential, store-operated, and receptor-operated calcium channels, particularly focusing on their regulatory functions and inherent interactions as well as calcium channels-related reagents and drugs, which is expected to bridge basic research and clinical applications in dermatologic diseases.

FRET Visualization of Cyclic Stretch-Activated ERK via Calcium Channels Mechanosensation While Not Integrin β1 in Airway Smooth Muscle Cells

“…This suggests that Ca 2+ channels on the plasma membrane had significant contributive role while not essential to the mechanical activation of ERK. However, by selective chemical inhibition of IP 3 R Ca 2+ channel with 2-APB, or SERCA pump with Thapsigargin on ER membrane ( Wang et al, 2021 ), the mechanical activation of ERK was almost blocked ( Figures 3C,D ), indicating that Ca 2+ release from the ER store had an essential role. In contrast, there was little effect on the ERK activation by inhibition of L-type Ca 2+ channel with nifedipine, or store-operated Ca 2+ channel (SOC) with LaCl 3 on plasma membrane ( Parekh and Putney, 2005 ; Wang et al, 2021 ) ( Figures 3E,F ).…”

“…However, by selective chemical inhibition of IP 3 R Ca 2+ channel with 2-APB, or SERCA pump with Thapsigargin on ER membrane ( Wang et al, 2021 ), the mechanical activation of ERK was almost blocked ( Figures 3C,D ), indicating that Ca 2+ release from the ER store had an essential role. In contrast, there was little effect on the ERK activation by inhibition of L-type Ca 2+ channel with nifedipine, or store-operated Ca 2+ channel (SOC) with LaCl 3 on plasma membrane ( Parekh and Putney, 2005 ; Wang et al, 2021 ) ( Figures 3E,F ). From statistical comparison of the FRET changes (in percentage) after 0.5 h stretch and total 1 h stretch ( Figure 3G ), inhibition of IP 3 R or SERCA pump on ER membrane had the most significant impact on the mechanical activation of ERK, followed by inhibiting extracellular Ca 2+ uptakes with reduced delayed response, while L-type Ca 2+ channel and SOC on the plasma membrane were not actively involved into the ERK activation.…”

Mechanotransduction in Skin Inflammation

“…Transient receptor potential (TRP) channels are implicated in the regulation of keratinocyte proliferation and differentiation, skin barrier and immune functions [191,194], and the sensation of inflammatory pain [195]. Their specific expression and non-neuronal cell functions in normal and diseased skin have been recently reviewed in [196]. The canonical TRP cation channels TRPC1, TRPC4, and TRPC6 are key regulators of calciuminduced keratinocyte differentiation.…”

“…Therapeutic approaches targeting mechanosensitive channels can be exploited in the management of highly prevalent skin conditions such as AD, psoriasis, and acne [196,197].…”

Mesenchymal Stem Cell-Derived Extracellular Vesicles: A Potential Therapy for Diabetes Mellitus and Diabetic Complications

“…A hyperglycemia-induced decline in healing ability makes the diabetic ulcer an important problem threatening the life and health of diabetic patients [ 105 ]. The traditional strategy relies on medical treatment and surgical blood flow reconstruction, whereas therapeutic efficacy is not satisfactory [ 106 ]. Recently, MSC-EVs have been widely utilized to accelerate diabetic wound healing.…”