ROLE OF TWO-PORES CHANNELS IN THE CONTROL OF HYDROMINERAL BALANCE

Essential for survival, hydromineral balance is maintained by the kidneys through controlled excretion and reabsorption of water and Na⁺, processes known as diuresis and natriuresis. Vasopressin is a neuropeptide synthesized and secreted by the hypothalamus and is a principal regulator of this process. Its secretion is tightly controlled by changes in plasma osmolarity and relies on intracellular calcium signaling. However, the calcium sources and signaling pathways that couple osmotic challenge to vasopressin release remain incompletely defined. In particular, the potential contribution of recently identified lysosomal calcium channels has not yet been investigated. We previously showed that deletion of the endolysosomal two-pore channels (TPCs) in mice leads to a marked reduction in plasma vasopressin levels. We therefore hypothesized that TPCs are involved in the maintenance of water balance. Consistent with this hypothesis, mice lacking TPCs displayed altered drinking behavior. We next examined the activity of vasopressin neurons using patch-clamp recordings in hypothalamic slices. Neurons were challenged with hypertonic solutions, revealing a reduced neuronal response in slices from TPC knockout mice, likely contributing to the impaired vasopressin secretion. Together, these findings establish TPCs as key regulators of vasopressin secretion and reveal a previously unrecognized lysosomal calcium mechanism required for osmotic activation of hypothalamic vasopressin neurons and the maintenance of systemic water balance.