The TRPM2 channel is a hypothalamic heat sensor that limits fever and can drive hypothermia

Abstract

Body temperature homeostasis is critical for survival and requires precise regulation by the nervous system. The hypothalamus serves as the principal thermostat that detects and regulates internal temperature. We demonstrate that the ion channel TRPM2 [of the transient receptor potential (TRP) channel family] is a temperature sensor in a subpopulation of hypothalamic neurons. TRPM2 limits the fever response and may detect increased temperatures to prevent overheating. Furthermore, chemogenetic activation and inhibition of hypothalamic TRPM2-expressing neurons in vivo decreased and increased body temperature, respectively. Such manipulation may allow analysis of the beneficial effects of altered body temperature on diverse disease states. Identification of a functional role for TRP channels in monitoring internal body temperature should promote further analysis of molecular mechanisms governing thermoregulation and foster the genetic dissection of hypothalamic circuits involved with temperature homeostasis.

Selective inhibition of TRPM2 channel by two novel synthesized ADPR analogues

“…The NUDT9‐homology (NUDT9‐H) domain serves a binding site for channel activation by adenosine 5′‐diphosphoribose (ADPR) 6. Accumulating evidence shows that TRPM2 channel plays a critical role in sensing internal body temperature9, 10, 11 and is also implicated in many pathological processes such as neurodegeneration,12, 13 diabetes14, 15 and ischemic reperfusion injury,16, 17 suggesting TRPM2 as a potential therapeutic target. Therefore, inhibiting TRPM2 may lead to a therapeutic potential for ischemicinjury.…”

Warm feelings for TRPM2

“…Using TRPM2-deficient mice, Song et al [2] were able to demonstrate that heat responses in WSNs are dependent on TRPM2. Interestingly, whereas in isolated WSNs temperatures in the range of 45 ºC were required to evoke robust responses, heat activation was shifted to significantly lower temperatures when analyzed in acute POA brain slices, where responses could be evoked by warming above ~38 ºC.…”

“…Whereas the (patho) physiology of thermoregulation has been extensively studied in the past decades, the molecular basis of the steep temperature sensitivity of POA neurons remained elusive. Now, in a recent study published in Science, Song et al [2] provide compelling evidence that TRPM2, a member of the transient receptor potential (TRP) superfamily of cation channels, acts as a heat sensor in warm-sensitive neurons (WSNs) of the POA.…”

“…The discovery that TRPM2 marks WSNs in the POA allowed Song et al [2] to pinpoint the role of these neurons in thermoregulation. In a first set of experiments, they investigated the consequences of eliminating TRPM2 on regulation of T core .…”

“…To identify WSNs, Song et al [2] performed intracellular calcium measurements in isolated POA neurons, and found that about one in six neurons exhibited a robust calcium response upon warming to 45 ºC. In their search for potential heat sensors underlying the heat responses in these WSNs, Song et al focused on known temperaturesensitive and calcium-permeable ion channels, mainly members of the TRP superfamily, and used various more or less selective pharmacological tools to evaluate their functional expression in POA neurons.…”