br Sensory systems and signaling
Sensory systems and signaling pathways of epidermal keratinocytes In the last decade, members of the transient receptor potential (TRP) family of receptors, which are activated at defined temperatures, have been cloned. These polymodal receptors were discovered mainly in the nervous system, where many of them act as sensors of temperature or other physical and chemical factors. Some of these TRP receptors are also expressed in epidermal topirimate manufacturer (Table 1). TRPV1 in epidermal keratinocytes is activated by temperature (>43°C), protons (pH < 6.6) and capsaicin. TRPV3 in epidermal keratinocytes is activated by oregano, thyme, and clove-derived flavor components, such as carvacrol, eugenol, and thymol. Interestingly, TRPV3 in epidermal keratinocytes is activated by camphor, whereas TRPV3 in sensory neurons is not. Thus, TRPV3 in epidermal keratinocytes might be a sensor of these herbal extracts. TRPV4 is activated by osmotic stimuli. We previously demonstrated that environmental humidity influences many aspects of epidermal homeostasis, and activation of TRPV4 accelerated epidermal permeability barrier recovery after barrier disruption. Thus, TRPV4 in epidermal keratinocytes might be a sensor of environmental humidity. We also recently demonstrated that mechanical stress induced elevation of intracellular calcium in cultured keratinocytes, and this elevation was blocked by a nonspecific TRP antagonist, ruthenium red. Thus, TRPs in keratinocytes might also serve as components of a cutaneous sensory system for external mechanical stimuli. Furthermore, TRPM8 in epidermal keratinocytes is activated at low temperature (<22°C) and by menthol, and similarly, TRPA1 in epidermal keratinocytes is activated at low temperature and by several chemical stimuli. Activation of TRPM8 and TRPA1 in epidermal keratinocytes accelerated barrier recovery after disruption. In addition, we have shown that a variety of environmental factors, including visible light, sound, and external electrical potential, influence epidermal permeability barrier homeostasis. These results led us to hypothesize that epidermal keratinocytes might also sense these environmental factors. Indeed, we found that photoreceptor-like proteins present in the retina are also expressed in epidermal keratinocytes. Voltage-gated calcium channels, which play a key role in the nervous system, are also expressed in keratinocytes. These, and perhaps other unidentified proteins, might be involved in other so far undiscovered sensory systems of epidermal keratinocytes. Thus, epidermal keratinocytes have sensory functions for a wide range of environmental factors, even though the full extent of these functions remains to be established. The next question is, are these signals from the environment passed to the nervous system? Indeed, various interactions between keratinocytes and the peripheral nervous system have been suggested. We demonstrated that excitation of keratinocytes was transferred to nerve fibers in a keratinocyte-neuron co-culture system. The effect was partially blocked by application of an adenosine triphosphate (ATP)-degrading enzyme, suggesting that ATP plays an important role in signal transmission from keratinocytes to the nervous system. Another study indicated that prostaglandin E(2) may also act as a messenger from keratinocytes to the nervous system.
Information processing Information derived from the environment is transferred by afferent nerve fibers to the central nervous system, and processed in the brain, with the aid of multiple neurotransmitters and specific receptors. We have shown that many of the neurotransmitter receptors originally found in the central nervous system are also expressed in epidermal keratinocytes. We also showed that glutamate, dopamine, and nitric oxide are released from keratinocytes immediately after insult of the stratum corneum; and these molecules are candidate messengers from keratinocytes to the nervous system. Interestingly, they also influence epidermal permeability barrier homeostasis. These findings are consistent with the idea that various communication modes between epidermal keratinocytes and the nervous system operate in the epidermis as a part of the cutaneous sensation system. Epidermal keratinocytes also generate many other messenger molecules, including neurotransmitters, neuropeptides, and hormones, which would be required for processing sensory information, and transmitting messages to the central nervous system.