CNGA3 acts as a cold sensor in hypothalamic neurons

Abstract

Most mammals maintain their body temperature around 37°C, whereas in hibernators it can approach 0°C without triggering a thermogenic response. The remarkable plasticity of the thermoregulatory system allowed mammals to thrive in variable environmental conditions and occupy a wide range of geographical habitats, but the molecular basis of thermoregulation remains poorly understood. Here we leverage the thermoregulatory differences between mice and hibernating thirteen-lined ground squirrels (Ictidomys tridecemlineatus) to investigate the mechanism of cold sensitivity in the preoptic area (POA) of the hypothalamus, a critical thermoregulatory region. We report that, in comparison to squirrels, mice have a larger proportion of cold-sensitive neurons in the POA. We further show that mouse cold-sensitive neurons express the cyclic nucleotide-gated ion channel CNGA3, and that mouse, but not squirrel, CNGA3 is potentiated by cold. Our data reveal CNGA3 as a hypothalamic cold sensor and a molecular marker to interrogate the neuronal circuitry underlying thermoregulation.

Glutamate–aspartate transporter 1 attenuates oxygen–glucose deprivation‐induced injury by promoting glutamate metabolism in primary cortical neurons

“…Previous studies have demonstrated that mammalian hibernators possess numerous cellular and molecular mechanisms that facilitate their survival in stress conditions (Feketa et al, 2020; Laursen et al, 2016; Matos‐Cruz et al, 2017; Singhal et al, 2020). However, the molecular basis for the neuronal tolerance of hibernators to brain ischemia remains poorly understood.…”

The Role of Cold-Sensitive Ion Channels in Peripheral Thermosensation

“…Apart from TRP channels, a few other types of ion channel have been proposed to function as cold sensors, including two-pore domain potassium channels (K2P; Maingret et al, 2000 ; Kang et al, 2005 ), epithelial sodium channels (ENaC; Askwith et al, 2001 ), GluK2 glutamate receptors (Gong et al, 2019 ), and CNGA3 cyclic nucleotide-gated ion channels (Feketa et al, 2020 ). The possible contribution of these ion channels to cold sensation will now be discussed.…”

“…Another novel candidate for the unidentified cold sensor is the cation channel CNGA3. CNGA3 is not directly gated by cold, but its activation by cGMP can by potentiated by cold below 22°C, with a Q 10 value of 6.5 (Feketa et al, 2020 ). The cation channel CNGA3 was first discovered to be cold-sensitive in Grünenberg ganglion neurons, located in the vestibule of the murine nose (Stebe et al, 2014 ).…”

“…These neurons transduce coolness via a cGMP cascade (Mamasuew et al, 2010 ). Additionally, CNGA3 is responsible for cold responses of a subpopulation of neurons in the thermoregulatory center of the hypothalamus in mice (Feketa et al, 2020 ). Interestingly, CNGA3 is also enriched in a subpopulation of cold-sensitive DRG neurons (Luiz et al, 2019 ).…”

Transcriptional regulation of intermolecular Ca 2+ signaling in hibernating ground squirrel cardiomyocytes: The myocardin–junctophilin axis

“…Hibernation is an adaptation of some small animals and birds to survive the cold winter. The body temperature of hibernating mammals, normally maintained at or near 37°C in the euthermic state, is down-regulated to the environmental level (18)(19)(20)(21) possibly through certain hypothalamic neuronal circuits (22)(23)(24). Sustained hypothermia usually disrupts intracellular homeostasis of Ca 2+ in nonhibernating mammals (25)(26)(27)(28)(29).…”