Abstract
The Scn7A gene encodes NaX, an atypical non-inactivating Na+ channel whose expression in sensory circumventricular organs is essential to maintain homeostatic responses for body fluid balance. However, NaX has also been detected in homeostatic effector neurons, such as vasopressin (VP) releasing magnocellular neurosecretory cells (MNCVP) which secrete VP (antidiuretic hormone) into the bloodstream in response to hypertonicity and hypernatremia. Yet, the physiological relevance of NaX expression in these effector cells remains unclear. Here we show that rat MNCVP in males and females are depolarized and excited in proportion with isosmotic increases in [Na+]. These responses were caused by an inward current resulting from a cell-autonomous increase in Na+ conductance. The Na+-evoked current was unaffected by blockers of other Na+-permeable ion channels but was significantly reduced by shRNA-mediated knockdown of Scn7A expression. Furthermore, reducing the density of NaX channels selectively impaired the activation of MNCVP by systemic hypernatremia without affecting their responsiveness to hypertonicity in vivo. These results identify NaX as a physiological Na+ sensor whose expression in MNCVP contributes to the generation of homeostatic responses to hypernatremia.
Significance Statement
In this study, we provide the first direct evidence showing that the sodium-sensing channel encoded by the Scn7A gene (NaX) mediates cell-autonomous sodium detection by magnocellular neurosecretory cells (MNCs) in the low millimolar range and that selectively reducing the expression of these channels in MNCs, impairs their activation in response to a physiologically relevant sodium stimulus in vitro and in vivo. These data reveal that NaX operates as a sodium sensor in these cells and that the endogenous sensory properties of osmoregulatory effector neurons contribute to their homeostatic activation in vivo.
Footnotes
The authors declare there are no conflicts of interest.
This work was supported by a Foundation Grant from the Canadian Institutes of Health Research (CIHR; FDN 143337), an infrastructure grant from the Canada Foundation for Innovation and a James McGill Chair to C.W.B., as well as financial support from the Centro de Investigacion y de Estudios Avanzados (CINVESTAV) to U.G.H. Additional support was received in the form of a CINVESTAV studentship (S.J.S.M.) and a studentship from the McGill University Healthy Brains for Healthy Lives program (J.C.W.). The Research Institute of the McGill University Health Center (RIMUHC) receives generous funding from the Fonds de Recherche Québec Santé.
