Ammonium in nervous tissue: transport across cell membranes, fluxes from neurons to glial cells, and role in signalling

Most, but not all, animal cell membranes are permeable to NH3, the neutral, minority form of ammonium which is in equilibrium with the charged majority form NH4+. NH4+ crosses many cell membranes via ion channels or on membrane transporters, and cultured mammalian astrocytes and glial cells of bee retina take up NH4+ avidly, in the latter case on a Cl−-cotransporter selective for NH4+ over K+. In bee retina, a flux of ammonium from neurons to glial cells is an essential component of energy metabolism, which involves a flux of alanine from glial cells to neurons. In mammalian brain, both glutamate and ammonium are taken up preferentially by astrocytes and form glutamine. Glutamine is transferred to neurons where it is deamidated to re-form glutamate; the maintenance of this cycle appears to require a substantial flux of ammonium from neurons to astrocytes. In addition to maintaining the glial cell content of fixed N (a 'bookkeeping' function), ammonium is expected to participate in the regulation of glial cell metabolism (a signalling function): it will increase conversion of glutamate to glutamine, and, by activating phosphofructokinase and inhibiting the α-ketoglutarate dehydrogenase complex, it will tend to increase the formation of lactate.