To survive, cells and organisms must regulate concentrations of Na+ within a range compatible with physiological functions. Shimizu et al. show that Na+ sensing occurs in part through an unusual mechanism in the mammalian brain in which neuronal activity is controlled by associated glial cells. Mammals appear to sense Na+ concentrations in the blood through special brain structures known as circumventricular organs, in particular the subfornical organ (SFO), where a blood-brain barrier is not present, allowing cells to sense the chemical makeup of the blood. Sodium channels known as Nax channels are required for proper behavioral responses to excess Na+, but these channels are expressed on astrocytes rather than neurons. The authors used a yeast two-hybrid screen to detect proteins that interacted with the cytoplasmic domain of Nax. One of the interacting proteins was identified as the cell membrane sodium pump (Na+/K+-ATPase). In cultured cells expressing Nax, increased concentrations of extracellular Na+ caused increased activity of the Na+/K+-ATPase. Suspecting that the association of Nax with the Na+/K+-ATPase might influence cellular energy metabolism, the authors showed that exposure of slices from the SFO of wild-type mice to excessive extracellular Na+ caused an increase in glucose uptake that was absent in SFO slices from animals lacking Nax. This enhanced glucose use led to increased lactate secretion in the slices. The lactate in turn was found to increase the firing frequency of GABAergic neurons in the SFO slices. The effect on the neurons was reduced when activity of the transporter that carries lactate into the neurons was inhibited. Thus, the authors conclude that Na+ sensing in the SFO results from glial cells that are the key sensors, which then signal to neighboring neurons by secretion of lactate. Commentary by Iadecola places the work in the context of other instances of lactate signaling in neurons and other physiological mechanisms that cooperate to keep Na+ concentrations in check.
H. Shimizu, E. Watanabe, T. Y. Hiyama, A. Nagakura, A. Fujikawa, H. Okado, Y. Yanagawa, K. Obata, M. Noda, Glial Nax channels control lactate signaling to neurons for brain [Na+] sensing. Neuron 54, 59-72 (2007). [Online Journal]
C. Iadecola, Astrocytes take center stage in salt sensing. Neuron 54, 3-5 (2007). [Online Journal]