Transient Receptor Potential ion channels (TRPs) have been described as polymodal sensors, being responsible for transducing a wide variety of stimuli, and being involved in sensory functions such as chemosensation, thermosensation, mechanosensation, and photosensation. Mechanical and chemical stresses exerted on the membrane can be transduced by specialized proteins into meaningful intracellular biochemical signaling, resulting in physiological changes. Of particular interest are compounds that can change the local physical properties of the membrane, thereby affecting nearby proteins, such as TRP channels, which are highly sensitive to the membrane environment. In this review, we provide an overview of the current knowledge of TRP channel activation as a result of changes in the membrane properties induced by amphipathic structural lipidic components such as cholesterol and diacylglycerol, and by exogenous amphipathic bacterial endotoxins.

The cellular and systemic effects induced by bacterial lipopolysaccharides (LPS) have been solely attributed to the activation of the Toll-like receptor 4 (TLR4) signalling cascade. However, recent studies have shown that LPS activates several members of the Transient Receptor Potential (TRP) family of cation channels. Indeed, LPS induces activation of the broadly-tuned chemosensor TRPA1 in sensory neurons in a TLR4-independent manner, and genetic ablation of this channel reduced mouse pain and inflammatory responses triggered by LPS and the gustatory-mediated avoidance to LPS in fruit flies. LPS was also shown to activate TRPV4 channels in airway epithelial cells, an effect leading to an immediate production of bactericidal nitric oxide and to an increase in ciliary beat frequency. In this review, we discuss the role of TRP channels as sensors of bacterial endotoxins, and therefore, as crucial players in the timely detection of invading gram-negative bacteria.

Free nerve endings are key structures in sensory transduction of noxious stimuli. In spite of this, little is known about their functional organization. Transient receptor potential (TRP) channels have emerged as key molecular identities in the sensory transduction of pain-producing stimuli, yet the vast majority of our knowledge about sensory TRP channel function is limited to data obtained from in vitro models which do not necessarily reflect physiological conditions. In recent years, the development of novel optical methods such as genetically encoded calcium indicators and photo-modulation of ion channel activity by pharmacological tools has provided an invaluable opportunity to directly assess nociceptive TRP channel function at the nerve terminal.

The role of TRPA1 in the thermosensitivity of the corneal cold thermoreceptor nerve endings was studied in young and aged mice. The contribution of the TRPA1-dependent activity to basal tearing and thermally-evoked blink was also explored. The corneal cold thermoreceptors’ activity was recorded extracellularly in young (5-month-old) and aged (18-month-old) C57BL/6WT (WT) and TRPA1^−/− knockout (TRPA1-KO) mice at basal temperature (34 °C) and during cooling (15 °C) and heating (45 °C) ramps. The blink response to cold and heat stimulation of the ocular surface and the basal tearing rate were also measured in young animals using orbicularis oculi muscle electromyography (OOemg) and phenol red threads, respectively. The background activity at 34 °C and the cooling- and heating-evoked responses of the cold thermoreceptors were similar in WT and TRPA1-KO animals, no matter the age. Similar to the aged WT mice, in the young and aged TRPA1-KO mice, most of the cold thermoreceptors presented low frequency background activity, a low cooling threshold, and a sluggish response to heating. The amplitude and duration of the OOemg signals correlated with the magnitude of the induced thermal change in the WT but not in the TRPA1-KO mice. The basal tearing was similar in the TRPA1-KO and WT mice. The electrophysiological data suggest that the TRPA1-dependent nerve activity, which declines with age, contributes to detecting the warming of the ocular surface and also to integrating the thermally-evoked reflex blink.

Background and Purpose: The functional organization of corneal cold nerve endings, critical structures in maintaining the ocular surface, remains poorly understood. Here, the photoisomerizable small‐molecule diethylamine‐azobenzene‐quaternary ammonium (DENAQ) was used to photomodulate activity of cold‐sensing nerve terminals in control and chronic tear‐deficient corneas. Furthermore, DENAQ was used for in vivo photochemical regulation of the thermally induced blink reflex. Experimental Approach: Extracellular nerve terminal impulse activity was recorded on cold terminals in excised corneas of naïve and tear‐deficient guinea pigs pre‐incubated with DENAQ. Pulses of light at a wavelength of 460 nm were delivered to the perfused corneas. The thermally induced blink reflex was assessed using orbicularis oculi electromyography in anaesthetised rats after topical administration of DENAQ to the eye under blue light and darkness conditions. Key Results: Exposure to blue light robustly reduced spontaneous activity of both naïve and tear‐deficient cold nerve terminals pre‐incubated with DENAQ, while cold‐evoked responses remained unaffected. Pre‐incubation of excised corneas with DENAQ, along with pharmacological P2X receptor antagonists, prevented the DENAQ‐mediated photoreduction of the cold nerve terminal spontaneous activity. In addition, blue light increased cold‐evoked reflex blink in eyes pre‐treated with DENAQ. Conclusion and Implications: DENAQ enters guinea pig cold sensory nerve endings primarily through P2X channels in excised corneas. Subsequently, DENAQ decreases the spontaneous nerve terminal impulse activity upon light irradiation by modulating voltage‐gated potassium (K _V ) channel activity. Furthermore, the cold‐evoked blink reflex is modulated by light in DENAQ‐treated eyes. Chemical photoswitches like DENAQ might be potential new treatments for ocular discomfort and pain in dry eye disease.