A Critical Role for TRP Channels in the Skin

The transient receptor potential (TRP) channels were first described in , in which photoreceptors carrying gene mutations exhibited a transient voltage response to continuous light stimulation (Minke, 1977; Montell et al., 1985). Mammalian TRP channels have six subfamilies including TRPC, TRPV, TRPM, TRPA, TRPML, and TRPP (Clapham, 2003), with about 28 mammalian subfamily members, most of which have splicing variants. All TRP channels have six transmembrane domains with the N- and C-terminal regions located inside the cell and are assembled as tetramers to form nonselective cation-permeable pores (Liao et al., 2014). TRP channels are expressed in a wide variety of tissues, and they are commonly embedded either in the membrane surface or cytosolic organelles, such as endosomes and lysosomes. Activation of TRP channels generally promotes excitability of excitable cells and Ca influx in many forms of cellular processes in both excitable and nonexcitable cells. The skin is divided into three layers: (1) The epidermis, the outermost layer of skin, provides a waterproof barrier and creates the skin tone. Although the most abundant cells of the epidermis are keratinocytes, there are also nonepithelial immune cells present in the epidermis, such as Langerhans cells and dendritic epidermal T cells (DETCs). (2) The dermis, directly under the epidermis, contains tough connective tissue, hair follicles (HFs), and sweat glands. The dermis also hosts different subtypes of T cells that recirculate through skin-draining lymph nodes and are involved in normal immunity as well as inflammatory skin diseases such as psoriasis (Bos et al., 1987; Streilein, 1983). In addition to T cells, the dermis is enriched with tissue macrophages and dendritic cells that originate from the yolk sac and self-renew within the skin under inflammatory conditions (Jenkins, 2011). Together with cutaneous innate immune cells, the circulating monocytes traffic through the skin to survey the environment and transport antigens to the draining lymph nodes (Jakubzick et al., 2013). (3) The deeper subcutaneous tissue (hypodermis) is made of fat and connective tissue. In the skin, TRP channels are not only expressed in sensory nerve endings but also in many nonneuronal cell populations including keratinocytes and skin-resident immune cells (Figure 6.1). Various TRP channels participate in the formation and maintenance of skin barrier, HF growth, and cutaneous immunological and inflammatory processes, thereby maintaining skin homeostasis as well as contributing to many types of skin disorders (Figure 6.2). More importantly, several skin-expressing TRP channels act as the first-order sensors of temperature, mechanical, and chemical stimuli and mediate our senses of temperature, touch, itch, and pain under both physiological and pathological conditions.