The Hypothermic Effect of Hydrogen Sulfide Is Mediated by the Transient Receptor Potential Ankyrin-1 Channel in Mice.

Emoke Olah,Andras Garami,Kata Fekete,Valeria Tekus,Leonardo Kelava,Balazs Gaszner,Hannah V Wilson,Matthew Whiteman,Margit Solymar,Eszter Pakai,Erika Pinter,Patrik Keringer,Zoltan Rumbus,Viktoria Kormos,Julie Keeble

doi:10.3390/ph14100992

Abstract

Hydrogen sulfide (H2S) has been shown in previous studies to cause hypothermia and hypometabolism in mice, and its thermoregulatory effects were subsequently investigated. However, the molecular target through which H2S triggers its effects on deep body temperature has remained unknown. We investigated the thermoregulatory response to fast-(Na2S) and slow-releasing (GYY4137) H2S donors in C57BL/6 mice, and then tested whether their effects depend on the transient receptor potential ankyrin-1 (TRPA1) channel in Trpa1 knockout (Trpa1−/−) and wild-type (Trpa1+/+) mice. Intracerebroventricular administration of Na2S (0.5–1 mg/kg) caused hypothermia in C57BL/6 mice, which was mediated by cutaneous vasodilation and decreased thermogenesis. In contrast, intraperitoneal administration of Na2S (5 mg/kg) did not cause any thermoregulatory effect. Central administration of GYY4137 (3 mg/kg) also caused hypothermia and hypometabolism. The hypothermic response to both H2S donors was significantly (p < 0.001) attenuated in Trpa1−/− mice compared to their Trpa1+/+ littermates. Trpa1 mRNA transcripts could be detected with RNAscope in hypothalamic and other brain neurons within the autonomic thermoeffector pathways. In conclusion, slow- and fast-releasing H2S donors induce hypothermia through hypometabolism and cutaneous vasodilation in mice that is mediated by TRPA1 channels located in the brain, presumably in hypothalamic neurons within the autonomic thermoeffector pathways.

Highlights

Since in our experiments we showed that the hypothermic response is triggered from the central nervous system, we focused our attention on the expression of the transient receptor potential ankyrin-1 (TRPA1) channel in the brain
We show that slow- and fast-releasing H2 S donors induce hypothermia through hypometabolism and cutaneous vasodilation in mice and that the hypothermic effect of H2 S is mediated by TRPA1 channels located in the brain, presumably on hypothalamic neurons within the autonomic thermoeffector pathways
Our findings highlight the importance of central TRPA1-mediated H2 S signaling in the thermoregulation system

Summary

Introduction

Hydrogen sulfide (H2 S) was considered to be an environmental toxin before it was identified as an endogenously produced mediator in the 1940s (for a review, see [1]). H2 S is recognized as an important gasotransmitter, which plays roles in a wide spectrum of physiological processes in the brain as well as in peripheral tissues in health and disease [2,3]. H2 S is synthesized both centrally and peripherally by specific enzymes including cystathionine β-synthase, cystathionine γ-lyase, and 3-mercaptopyruvate sulfurtransferase, but alternative H2 S-producing pathways are known [3,4].

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