Significance Adaptation to more severe ambient temperature fluctuations can be considered one of the key innovations of terrestrial tetrapods. Our study shows the formation of the functional MHR1-3 domain in transient receptor potential melastatin 8 (TRPM8) bestowed the channel with cold sensitivity during the water-to-land transition. The evolved MHR1-3 domain found in terrestrial tetrapods serves as an independent apparatus with cold sensitivity. Furthermore, this domain with independent cold sensitivity is necessary for the regulatory mechanism of the pore domain, where the efficacy of cold activation is largely altered by evolutionary tuning of the hydrophobicity of several residues during the diversification of terrestrial tetrapods. Our findings advance the understanding of cold-sensing emergence during evolution and the thermodynamic basis of TRPM8 cold activation.
Organisms from cyanobacteria to humans have evolved a wide array of photoreceptive strategies to detect light. Sunlight avoidance behavior is common in animals without vision or known photosensory genes. While indirect light perception via photothermal conversion is a possible scenario, there is no experimental evidence for this hypothesis. Here, we show a nonvisual and extraocular sunlight detection mechanism by identifying the broad-range thermal receptor 1 (BRTNaC1, temperature range = 33 to 48 °C) in centipede antennae. BRTNaC1, a heat-activated cation-permeable ion channel, is structurally related to members of the epithelial sodium channel family. At the molecular level, heat activation of BRTNaC1 exhibits strong pH dependence controlled by two protonatable sites. Physiologically, temperature-dependent activation of BRTNaC1 upon sunlight exposure comes from a striking photothermal effect on the antennae, where a slightly acidic environment (pH 6.1) of the body fluid leads to the protonation of BRTNaC1 and switches on its high thermal sensitivity. Furthermore, testosterone potently inhibits heat activation of BRTNaC1 and the sunlight avoidance behavior of centipedes. Taken together, our study suggests a sophisticated strategy for nonvisual sunlight detection in myriapods.
Temperature influences all biological processes. In wild animals, the evolution of molecular thermosensors is crucial in ambient temperature adaption and habitat selection with species specificity. The transient receptor potential melastatin 8 (TRPM8, the most established cold receptor expressed in thermosensory nerve endings) is a cation permeable ion channel, which plays a critical role in thermal sensation and adaptation. The transition of TRPM8 from the closed to open state can be attributed to strong cold dependence. Comparative studies of TRPM8 orthologs have provided valuable insights into how thermosensation has evolved in wild vertebrates over time. Specifically, the appearance of the trpm8 gene in lungfishes provided a protogene structure without function. During the water‐to‐land transition, the trpm8 protogene accumulated mutations mainly in the MHR1‐3 domain that confer cold sensitivity to TRPM8 proteins of terrestrial vertebrates. Furthermore, trpm8 in terrestrial vertebrates acquired mutations at the pore domain that resulted in a change in cold activation efficacy at the molecular level. In marine mammals, TRPM8 orthologs are cold‐sensitive, based on the expectation that the MHR1‐3 domain and pore domain are consistent with those of terrestrial mammals. This review discusses the relationship between the biophysical properties of TRPM8 cold activation and ambient temperature adaptation in vertebrates.
The skin secretion of tree frogs contains a vast array of bioactive chemicals for repelling predators, but their structural and functional diversity is not fully understood. Paxilline (PAX), a compound synthesized by Penicillium paxilli, has been known as a specific antagonist of large conductance Ca2+-activated K+ Channels (BKCa). Here, we report the presence of PAX in the secretions of tree frogs (Hyla japonica) and that this compound has a novel function of inhibiting the potassium channel subfamily K member 18 (KCNK18) channels of their predators. The PAX-induced KCNK18 inhibition is sufficient to evoke Ca2+ influx in charybdotoxin-insensitive DRG neurons of rats. By forming π-π stacking interactions, four phenylalanines located in the central pore of KCNK18 stabilize PAX to block the ion permeation. For PAX-mediated toxicity, our results from animal assays suggest that the inhibition of KCNK18 likely acts synergistically with that of BKCa to elicit tingling and buzzing sensations in predators or competitors. These results not only show the molecular mechanism of PAX-KCNK18 interaction, but also provide insights into the defensive effects of the enriched PAX.
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