title: Control of Glutamate Transport by Extracellular Potassium: Basis for a Negative Feedback on Synaptic Transmission.
abstract: Glutamate and K+, both released during neuronal firing, need to be tightly regulated to ensure accurate synaptic transmission. Extracellular glutamate and K+ ([K+]o) are rapidly taken up by glutamate transporters and K+-transporters or channels, respectively. Glutamate transport includes the exchange of one glutamate, 3 Na+, and one proton, in exchange for one K+. This K+ efflux allows the glutamate binding site to reorient in the outwardly facing position and start a new transport cycle. Here, we demonstrate the sensitivity of the transport process to [K+]o changes. Increasing [K+]o over the physiological range had an immediate and reversible inhibitory action on glutamate transporters. This K+-dependent transporter inhibition was revealed using microspectrofluorimetry in primary astrocytes, and whole-cell patch-clamp in acute brain slices and HEK293 cells expressing glutamate transporters. Previous studies demonstrated that pharmacological inhibition of glutamate transporters decreases neuronal transmission via extrasynaptic glutamate spillover and subsequent activation of metabotropic glutamate receptors (mGluRs). Here, we demonstrate that increasing [K+]o also causes a decrease in neuronal mEPSC frequency, which is prevented by group II mGluR inhibition. These findings highlight a novel, previously unreported physiological negative feedback mechanism in which [K+]o elevations inhibit glutamate transporters, unveiling a new mechanism for activity-dependent modulation of synaptic activity.
authors.affiliation: Department of Fundamental Neurosciences, University of Lausanne, CH-1005 Lausanne, Switzerland.
authors.forename: Theresa S
authors.initials: TS
authors.lastname: Rimmele
authors.affiliation: Department of Fundamental Neurosciences, University of Lausanne, CH-1005 Lausanne, Switzerland.
authors.forename: Anne-Bérengère
authors.initials: AB
authors.lastname: Rocher
authors.affiliation: Department of Fundamental Neurosciences, University of Lausanne, CH-1005 Lausanne, Switzerland.
authors.forename: Joel
authors.initials: J
authors.lastname: Wellbourne-Wood
authors.affiliation: Department of Fundamental Neurosciences, University of Lausanne, CH-1005 Lausanne, Switzerland.|Cellular Imaging Facility, University of Lausanne, CH-1005 Lausanne, Switzerland.
authors.forename: Jean-Yves
authors.initials: JY
authors.lastname: Chatton
mesh_terms: D015763:2-Amino-5-phosphonovalerate / Q000494:pharmacology; D027322:Amino Acid Transport System X-AG / Q000235:genetics / Q000378:metabolism*; D000596:Amino Acids / Q000494:pharmacology; D000818:Animals; D000831:Animals, Newborn; D001224:Aspartic Acid / Q000031:analogs & derivatives / Q000494:pharmacology / Q000506:poisoning; D001253:Astrocytes / Q000166:cytology / Q000187:drug effects / Q000502:physiology; D002540:Cerebral Cortex / Q000166:cytology; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D045604:Extracellular Fluid / Q000378:metabolism*; D058787:GABA-A Receptor Antagonists / Q000494:pharmacology; D018698:Glutamic Acid / Q000494:pharmacology; D057809:HEK293 Cells; D006801:Humans; D008564:Membrane Potentials / Q000187:drug effects; D051379:Mice; D008810:Mice, Inbred C57BL; D009433:Neural Inhibition / Q000187:drug effects; D009474:Neurons / Q000187:drug effects / Q000502:physiology*; D011188:Potassium / Q000378:metabolism* / Q000494:pharmacology; D009435:Synaptic Transmission / Q000187:drug effects / Q000502:physiology*; D014966:Xanthenes / Q000494:pharmacology
chemical_list: C508240:(2S,3S)-3-(3-(4-(trifluoromethyl)benzoylamino)benzyloxy)aspartate; D027322:Amino Acid Transport System X-AG; D000596:Amino Acids; D018691:Excitatory Amino Acid Antagonists; D058787:GABA-A Receptor Antagonists; C114624:LY 341495; D014966:Xanthenes; D001224:Aspartic Acid; D018698:Glutamic Acid; D015763:2-Amino-5-phosphonovalerate; D011188:Potassium
keywords: astrocyte; electrophysiology; metabotropic glutamate receptors; sodium imaging