The protein TMEM63B allows mammals to feel thirsty, study finds

Thirst is a crucial physiological signal that contributes to the survival of humans and other animals, by allowing them to detect when they are dehydrated so that they can drink. Drinking is essential for survival and for maintaining the balance of fluids in the body, also known as water homeostasis.

The neural underpinnings of thirst and the maintenance of water homeostasis have been widely studied over the past decades. Nonetheless, until recently, neuroscientists had not yet identified the proteins that support the mammalian brain’s ability to detect changes in the concentration of sodium and other solutes in the bloodstream, initiating the drive to drink.

Researchers at Capital Medical University, Shenzhen Bay Laboratory and other institutes in China recently showed that the transmembrane protein TMEM63B could serve as a molecular “thirst sensor,” ultimately prompting mammals to drink when their bodies need fluids.

Their paper, published in Neurondeepens the current understanding of the intricate neuro-genetic processes contributing to the maintenance of water homeostasis in mammals.

“An increase in blood osmolality is thought to induce thirst by activating a hyperosmolar sensor expressed in the subfornical organ (SFO), but the molecular identity of this sensor remains elusive,” wrote Wenjie Zou, Siqi Deng and their colleagues in their paper.

“Here, we provide behavioral and functional evidence to show that TMEM63B functions as a mammalian hyperosmolar sensor for thirst in SFO neurons.”

TMEM63B, which stands for transmembrane protein 63B, is a protein that spans across the outer layer (i.e., membrane) of cells. As part of their study, the researchers carried out a series of experiments involving adult mice, which shed light on the role of this protein in the signaling of thirst.

“First, we showed that TMEM63B is expressed in SFO excitatory neurons and required for the neuronal responses to hypertonic stimulation,” wrote Zou, Deng and their colleagues.

“More importantly, heterologously expressed TMEM63B is activated by hypertonic stimuli, and point mutations can alter the reversal potential of the channel. Additionally, purified TMEM63B in liposomes exhibits osmolarity-gated currents. Finally, Tmem63b knockout mice have profound deficits in thirst, and deleting TMEM63B within SFO neurons recapitulated this phenotype.”

The findings gathered by Zou, Deng and their colleagues suggest that the protein TMEM63B responds to changes in osmolarity (i.e., the concentration of solutes in the blood). When osmolarity becomes too high, the protein appears to prompt neurons in the SFO to generate electrical activity, which elicits the feeling of thirst experienced by animals.

Notably, they also found that silencing the Tmem63b gene in mice impaired their ability to feel thirsty and thus seek water when necessary. This observation further highlights the crucial role of this gene for the maintenance of water homeostasis in the body, which is essential for the survival of all mammals.

“Taken together, these results provide a molecular basis for thirst and suggest that TMEM63B is a mammalian hyperosmolar sensor for thirst,” wrote Zou, Deng and their colleagues.

This recent study offers precious new insight into the mechanisms contributing to the survival of both humans and other mammals, which could be validated in further studies spanning across a wider range of species.

In addition to advancing the neuroscientific understanding of thirst, this insight unveils a new potential target for the treatment of rare genetic defects in fluid balance or thirst-related disorders.

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