Takaaki Sokabe

Perception of external thermal stimuli is critical to animal survival, and although an animal’s skin is the largest contact surface for thermal inputs, contributions of skin cells to noxious temperature sensing have not been extensively explored. Here, we show that exposure to heat transiently sensitizes Drosophila larvae to subsequent noxious stimuli. This sensitization is induced by prior stimulation of epidermal cells but not nociceptors, suggesting that epidermal cells modulate nociceptor function in response to heat exposure. Indeed, we found that Drosophila epidermal cells are intrinsically thermosensitive, exhibiting robust heat-off responses following warming to noxious temperatures as well as responses to cooling below comfortable temperatures. Further, we found that epidermal heat-off calcium responses involve influx of extracellular calcium and require the store-operated calcium channel Orai and its activator Stim. Finally, epidermal heat-off responses and heat-evoked nociceptive sensitization exhibit similar temperature dependencies, and we found that Stim and Orai are required in epidermal cells for heat-evoked nociceptive sensitization. Hence, epidermal thermosensory responses provide a form of adaptive sensitization to facilitate noxious heat avoidance.

Sensory inputs of temperature dynamics in the environment are essential for appropriate physiological outputs. The responsiveness of sensory neurons is maintained by functional thermosensor expression. However, the mechanism by which their expression is regulated is unclear. In this study, we identify a monoacylglycerol acyltransferase-coding gene named bishu-1 that contributes to maintaining the responsiveness of cool temperature sensing neurons in Drosophila. bishu-1 mutation leads to abnormal thermal avoidance in a cool temperature range. Cooling-induced responses in dorsal organ cool cells are weakened by the absence of bishu-1, and this is associated with reduced transcription of the ionotropic receptors IR25a and IR21a and a transcription factor broad. Our findings unveil a novel link between lipid metabolism and thermosensor function, thus providing new insights into mechanisms underlying the appropriate maintenance of sensory inputs.

In this review, we introduce the concept of “dual thermosensing mechanisms,” highlighting the functional collaboration between G protein‐coupled receptors (GPCRs) and transient receptor potential (TRP) channels that enable sophisticated cellular thermal responsiveness. GPCRs have been implicated in thermosensory processes, with recent findings identifying several candidates across species, including mammals, fruit flies, and nematodes. In many cases, these GPCRs work in conjunction with another class of thermosensors, TRP channels, offering insights into the complex mechanisms underlying thermosensory signaling. We examine how GPCRs function as thermosensors and how their signaling regulates cellular thermosensation, illustrating the complexity of thermosensory systems. Understanding these dual thermosensory mechanisms would advance our comprehension of cellular thermosensation and its regulatory pathways.

Sensory inputs of temperature dynamics in the environment are essential for appropriate physiological outputs. The responsiveness of sensory neurons is maintained by functional thermosensor expression. However, the mechanism by which their expression is regulated is unclear. In this study, we identified a monoacylglycerol acyltransferase-coding gene named bishu-1 that contributes to maintaining the responsiveness of cool temperature sensing neurons in Drosophila . bishu-1 mutation led to abnormal thermal avoidance in a cool temperature range. Cooling-induced responses in dorsal organ cool cells were weakened by the absence of bishu-1 , and this was associated with reduced transcription of the ionotropic receptors IR25a and IR21a through the transcription factor broad . Our findings unveil a novel link between lipid metabolism and thermosensor function, thus providing new insights into mechanisms underlying the appropriate maintenance of sensory inputs.

Animals must sense and acclimatize to environmental temperatures for survival, yet their thermosensing mechanisms other than transient receptor potential (TRP) channels remain poorly understood. We identify a trimeric G protein-coupled receptor (GPCR), SRH-40, which confers thermosensitivity in sensory neurons regulating temperature acclimatization in Caenorhabditis elegans. Systematic knockdown of 1000 GPCRs by RNAi reveals GPCRs involved in temperature acclimatization, among which srh-40 is highly expressed in the ADL sensory neuron, a temperature-responsive chemosensory neuron, where TRP channels act as accessorial thermoreceptors. In vivo Ca²⁺ imaging demonstrates that an srh-40 mutation reduced the temperature sensitivity of ADL, resulting in supranormal temperature acclimatization. Ectopically expressing SRH-40 in a non-warmth-sensing gustatory neuron confers temperature responses. Moreover, temperature-dependent SRH-40 activation is reconstituted in Drosophila S2R+ cells. Overall, SRH-40 may be involved in thermosensory signaling underlying temperature acclimatization. We propose a dual thermosensing machinery through a GPCR and TRP channels in a single sensory neuron.

Cell membranes hold an array of receptors and sensors to perceive environmental cues and translate them into intracellular signals. Lipid components play a crucial role, serving not only as a scaffold for receptors but also as essential intracellular signaling molecules. Signaling cascades involving receptors and lipids are fundamental to numerous biological reactions. Nowadays, the concept of ‘multimodal functions’ of receptors has gained attentions, especially following a discovery of thermo–sensitive TRP channels. Recently, I identified new lipid metabolites acting as a regulator of TRP channels downstream of light–activated rhodopsins in Drosophila. Moreover, these cascades from rhodopsins to TRP channels were found to function in both thermosensory neurons and taste neurons, indicating that their diverse roles in various cellular contexts. In this review, I will delve into the physiological functions of rhodopsins, lipid components, and TRP channels, highlighting the potential significance of the multimodality of sensory molecules.

Transient receptor potential (TRP) channels are primary sensory molecules in animals and are involved in detecting a diverse range of physical and chemical cues in the environments. Considering the crucial role of TRPA1 channels in nocifensive behaviors and aversive responses across various insect species, activators of TRPA1 are promising candidates for insect pest control. In this study, we demonstrate that 2-methylthiazoline (2MT), an artificial volatile thiazoline compound originally identified as a stimulant for mouse TRPA1, can be utilized as a novel repellent for fruit flies, Drosophila melanogaster. We observed that 2MT induced strong, dose-dependent avoidance behaviors in adult males, regardless of their feeding states, as well as egg laying behavior in females. These aversive responses were mediated by contact chemosensation via TrpA1 and olfaction via odorant receptors. Knocking down TrpA1 revealed the essential roles of bitter taste neurons and nociceptive neurons in the legs and labellum. Furthermore, among five isoforms, TrpA1-C and TrpA1-D exclusively contributed to the aversiveness of 2MT. We also discovered that these isoforms were directly activated by 2MT through covalent modification of evolutionarily conserved cysteine residues. In conclusion, we have identified 2MT as a stimulant for multiple sensory pathways, triggering aversive behaviors in fruit flies. We propose that 2MT and related chemicals may serve as potential resources for developing novel insect repellents.

Transient receptor potential (TRP) and PIEZO channels are known receptors for physical stimuli, such as temperature and mechanical touch, respectively, in sensory nerves. As these receptors are localized in the plasma membrane, the modulation of sensory receptor activity by plasma membrane lipids has recently attracted attention. In this study, we focused on ether phospholipids (ePLs), which are abundant in neurons, and analyzed their role in somatosensation using Drosophila as a model. Reduced mechanosensory behavior was observed with ePL synthesizing gene knockout or knockdown in mechano-sensitive PIEZO-expressing neurons. The activation of PIEZO channels was significantly augmented in the presence of ePLs. Furthermore, we observed that ePLs modulate the thermosensory behavior and reduce thermal threshold of the thermosensitive TRPA1 channels. Finally, we revealed that ePLs affect membrane tension and lipid order of the plasma membrane in culture cells. Our study identified ePLs as a modulator of multiple somatosensation modalities in Drosophila , which underscore the significance of functional interaction between membrane lipid and sensory channel proteins.