Perturbation of astroglial Slc38 glutamine transporters by NH ₄ ⁺ contributes to neurophysiologic manifestations in acute liver failure

Ammonia is considered the main pathogenic toxin in hepatic encephalopathy (HE). However, molecular mechanisms involved have been disputed. As altered glutamatergic and GABAergic neurotransmission has reported HE, we investigated whether four members of solute carrier 38 (Slc38) family amino acid transporters-involved replenishment glutamate GABA-contribute to ammonia neurotoxicity HE. We show that ammonium ion exerts multiple actions on Slc38 transporters: It competes with glutamine for binding system N transporters Slc38a3 Slc38a5, consequently inhibiting bidirectional astroglial transport. also H+ , Na+ K+ uncoupled permeation through same transporters, which may perturb intracellular pH, membrane potential, -buffering. Knockdown mice results cerebral cortical edema disrupted neurotransmitter synthesis mimicking events contributing HE development. Finally, a mouse model acute liver failure (ALF), demonstrate downregulation protein, impeded release, cytotoxic edema. Altogether, contribution ammonia-induced impairment recycling between astrocytes neurons, phenomenon underlying setting ALF.