TMEM63B functions as a mammalian hyperosmolar sensor for thirst

Thirst drives animals to reinstate water homeostasis by fluid intake. 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. Here, we provide behavioral and functional evidence to show that TMEM63B functions as a mammalian hyperosmolar sensor for thirst in SFO neurons. First, we showed that TMEM63B is expressed in SFO excitatory neurons and required for the neuronal responses to hypertonic stimulation. 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. Taken together, these results provide a molecular basis for thirst and suggest that TMEM63B is a mammalian hyperosmolar sensor for thirst.