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J Physiol
2017 Feb 01;5953:805-824. doi: 10.1113/JP273105.
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Na+ /H+ exchange via the Drosophila vesicular glutamate transporter mediates activity-induced acid efflux from presynaptic terminals.
Rossano AJ
,
Kato A
,
Minard KI
,
Romero MF
,
Macleod GT
.
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KEY POINTS: Intracellular pH regulation is vital to neurons as nerve activity produces large and rapid acid loads in presynaptic terminals. Rapid clearance of acid loads is necessary to maintain control of neurotransmission, but neuronal acid clearance mechanisms remain poorly understood. Glutamate is loaded into synaptic vesicles via the vesicular glutamate transporter (VGLUT), a mechanism conserved across phyla, and this study reports a previously unknown role for VGLUT as an acid-extruding protein when deposited in the plasmamembrane during exocytosis. The finding was made in Drosophila (fruit fly) larval motor neurons through a combined pharamacological and genetic dissection of presynaptic pH homeostatic mechanisms. A dual role for VGLUT serves to integrate neuronal activity and pH regulation in presynaptic nerve terminals.
ABSTRACT: Neuronal activity can result in transient acidification of presynaptic terminals, and such shifts in cytosolic pH (pHcyto ) probably influence mechanisms underlying forms of synaptic plasticity with a presynaptic locus. As neuronal activity drives acid loading in presynaptic terminals, we hypothesized that the same activity might drive acid efflux mechanisms to maintain pHcyto homeostasis. To better understand the integration of neuronal activity and pHcyto regulation we investigated the acid extrusion mechanisms at Drosophila glutamatergic motorneuron terminals. Expression of a fluorescent genetically encoded pH indicator, named 'pHerry', in the presynaptic cytosol revealed acid efflux following nerve activity to be greater than that predicted from measurements of the intrinsic rate of acid efflux. Analysis of activity-induced acid transients in terminals deficient in either endocytosis or exocytosis revealed an acid efflux mechanism reliant upon synaptic vesicle exocytosis. Pharmacological and genetic dissection in situ and in a heterologous expression system indicate that this acid efflux is mediated by conventional plasmamembrane acid transporters, and also by previously unrecognized intrinsic H+ /Na+ exchange via the Drosophila vesicular glutamate transporter (DVGLUT). DVGLUT functions not only as a vesicular glutamate transporter but also serves as an acid-extruding protein when deposited on the plasmamembrane.
Arosio,
Simultaneous intracellular chloride and pH measurements using a GFP-based sensor.
2010, Pubmed
Arosio,
Simultaneous intracellular chloride and pH measurements using a GFP-based sensor.
2010,
Pubmed
Baines,
Postsynaptic expression of tetanus toxin light chain blocks synaptogenesis in Drosophila.
1999,
Pubmed
Balcar,
Stereospecificity of the inhibition of L-glutamate and L-aspartate high affinity uptake in rat brain slices by threo-3-hydroxyaspartate.
1977,
Pubmed
Boron,
Intracellular pH transients in squid giant axons caused by CO2, NH3, and metabolic inhibitors.
1976,
Pubmed
Brand,
Targeted gene expression as a means of altering cell fates and generating dominant phenotypes.
1993,
Pubmed
Brown,
Light induced changes of internal pH in a barnacle photoreceptor and the effect of internal pH on the receptor potential.
1979,
Pubmed
Caldwell,
Presynaptic pH and vesicle fusion in Drosophila larvae neurones.
2013,
Pubmed
Chesler,
The regulation and modulation of pH in the nervous system.
1990,
Pubmed
Chu,
Endothelin(B) receptor activates NHE-3 by a Ca2+-dependent pathway in OKP cells.
1996,
Pubmed
Danbolt,
Glutamate uptake.
2001,
Pubmed
Daniels,
Increased expression of the Drosophila vesicular glutamate transporter leads to excess glutamate release and a compensatory decrease in quantal content.
2004,
Pubmed
Daniels,
Increased vesicular glutamate transporter expression causes excitotoxic neurodegeneration.
2011,
Pubmed
Daniels,
A single vesicular glutamate transporter is sufficient to fill a synaptic vesicle.
2006,
Pubmed
Dason,
A novel extraction protocol to probe the role of cholesterol in synaptic vesicle recycling.
2014,
Pubmed
Dow,
The multifunctional Drosophila melanogaster V-ATPase is encoded by a multigene family.
1999,
Pubmed
Dubreuil,
The Drosophila Anion Exchanger (DAE) lacks a detectable interaction with the spectrin cytoskeleton.
2010,
Pubmed
Endres,
Excitatory amino acids and intracellular pH in motoneurons of the isolated frog spinal cord.
1986,
Pubmed
Feng,
A modified minimal hemolymph-like solution, HL3.1, for physiological recordings at the neuromuscular junctions of normal and mutant Drosophila larvae.
2004,
Pubmed
Fujioka,
Even-skipped, acting as a repressor, regulates axonal projections in Drosophila.
2003,
Pubmed
Gagliardi,
Inhibitors of endocytosis prevent Wnt/Wingless signalling by reducing the level of basal β-catenin/Armadillo.
2014,
Pubmed
Giannakou,
Characterization of the Drosophila melanogaster alkali-metal/proton exchanger (NHE) gene family.
2001,
Pubmed
Goh,
Presynaptic regulation of quantal size: K+/H+ exchange stimulates vesicular glutamate transport.
2011,
Pubmed
Green,
Regulation of cAMP-stimulated ion current by intracellular pH, Ca2+, and calmodulin blockers.
1988,
Pubmed
Harper,
Dynamin inhibition blocks botulinum neurotoxin type A endocytosis in neurons and delays botulism.
2011,
Pubmed
Harvey,
NHE(VNAT): an H+ V-ATPase electrically coupled to a Na+:nutrient amino acid transporter (NAT) forms an Na+/H+ exchanger (NHE).
2009,
Pubmed
,
Xenbase
Hill,
Vestibular hair bundles control pH with (Na+, K+)/H+ exchangers NHE6 and NHE9.
2006,
Pubmed
Ito,
Na+/H+ and Na+/NH+4 activities of zebrafish NHE3b expressed in Xenopus oocytes.
2014,
Pubmed
,
Xenbase
Jan,
Properties of the larval neuromuscular junction in Drosophila melanogaster.
1976,
Pubmed
Johnson,
Proton: substrate stoichiometries during active transport of biogenic amines in chromaffin ghosts.
1981,
Pubmed
Kandasamy,
Plasma membrane Na+/H+ exchanger isoforms (NHE-1, -2, and -3) are differentially responsive to second messenger agonists of the protein kinase A and C pathways.
1995,
Pubmed
Koivusalo,
Amiloride inhibits macropinocytosis by lowering submembranous pH and preventing Rac1 and Cdc42 signaling.
2010,
Pubmed
Krizaj,
Intracellular pH modulates inner segment calcium homeostasis in vertebrate photoreceptors.
2011,
Pubmed
Kuromi,
Exocytosis and endocytosis of synaptic vesicles and functional roles of vesicle pools: lessons from the Drosophila neuromuscular junction.
2005,
Pubmed
Leem,
Characterization of intracellular pH regulation in the guinea-pig ventricular myocyte.
1999,
Pubmed
Lukashova,
The Na(+)/H (+) exchanger NHE5 is sorted to discrete intracellular vesicles in the central and peripheral nervous systems.
2013,
Pubmed
Macleod,
Fast calcium signals in Drosophila motor neuron terminals.
2002,
Pubmed
Macleod,
Synaptic vesicles: test for a role in presynaptic calcium regulation.
2004,
Pubmed
Maycox,
Glutamate uptake by brain synaptic vesicles. Energy dependence of transport and functional reconstitution in proteoliposomes.
1988,
Pubmed
Miesenböck,
Visualizing secretion and synaptic transmission with pH-sensitive green fluorescent proteins.
1998,
Pubmed
Nachshen,
The regulation of cytosolic pH in isolated presynaptic nerve terminals from rat brain.
1988,
Pubmed
Ohgaki,
Organellar Na+/H+ exchangers: novel players in organelle pH regulation and their emerging functions.
2011,
Pubmed
Omote,
Vesicular neurotransmitter transporter: bioenergetics and regulation of glutamate transport.
2011,
Pubmed
Pfeiffer,
Refinement of tools for targeted gene expression in Drosophila.
2010,
Pubmed
Poskanzer,
Synaptotagmin I is necessary for compensatory synaptic vesicle endocytosis in vivo.
2003,
Pubmed
Preobraschenski,
Vesicular glutamate transporters use flexible anion and cation binding sites for efficient accumulation of neurotransmitter.
2014,
Pubmed
Romero,
Cloning and functional expression of rNBC, an electrogenic Na(+)-HCO3- cotransporter from rat kidney.
1998,
Pubmed
,
Xenbase
Romero,
Cloning and characterization of a Na+-driven anion exchanger (NDAE1). A new bicarbonate transporter.
2000,
Pubmed
,
Xenbase
Roseth,
Uptake of L-glutamate into synaptic vesicles: competitive inhibition by dyes with biphenyl and amino- and sulphonic acid-substituted naphthyl groups.
1998,
Pubmed
Rossano,
Genetically encoded pH-indicators reveal activity-dependent cytosolic acidification of Drosophila motor nerve termini in vivo.
2013,
Pubmed
Rossano,
Loading Drosophila nerve terminals with calcium indicators.
2007,
Pubmed
Sánchez-Armass,
Regulation of pH in rat brain synaptosomes. I. Role of sodium, bicarbonate, and potassium.
1994,
Pubmed
Saroussi,
Vacuolar H(+)-ATPase-an enzyme for all seasons.
2009,
Pubmed
Schenck,
A chloride conductance in VGLUT1 underlies maximal glutamate loading into synaptic vesicles.
2009,
Pubmed
Schwiening,
Depolarization-induced pH microdomains and their relationship to calcium transients in isolated snail neurones.
2002,
Pubmed
Seidler,
pHi and HCO3- dependence of proton extrusion and Cl(-)-base exchange rates in isolated rabbit parietal cells.
1994,
Pubmed
Shaner,
Improved monomeric red, orange and yellow fluorescent proteins derived from Discosoma sp. red fluorescent protein.
2004,
Pubmed
Smith,
Functional determinants in the autoinhibitory domain of calcium/calmodulin-dependent protein kinase II. Role of His282 and multiple basic residues.
1992,
Pubmed
Svichar,
Preemptive regulation of intracellular pH in hippocampal neurons by a dual mechanism of depolarization-induced alkalinization.
2011,
Pubmed
Sweeney,
Targeted expression of tetanus toxin light chain in Drosophila specifically eliminates synaptic transmission and causes behavioral defects.
1995,
Pubmed
Thomas,
Intracellular pH measurements in Ehrlich ascites tumor cells utilizing spectroscopic probes generated in situ.
1979,
Pubmed
Tombaugh,
Differential sensitivity to intracellular pH among high- and low-threshold Ca2+ currents in isolated rat CA1 neurons.
1997,
Pubmed
Torroja,
Neuronal overexpression of APPL, the Drosophila homologue of the amyloid precursor protein (APP), disrupts axonal transport.
1999,
Pubmed
Tosco,
Calmodulin-mediated regulation of bicarbonate and lactate transports in rat jejunum.
2002,
Pubmed
Trapp,
Acidosis of hippocampal neurones mediated by a plasmalemmal Ca2+/H+ pump.
1996,
Pubmed
van der Bliek,
Dynamin-like protein encoded by the Drosophila shibire gene associated with vesicular traffic.
1991,
Pubmed
Venkatachalam,
VGLUT soothes the sour synapse.
2018,
Pubmed
Vila-Petroff,
Ca(2+)/calmodulin-dependent protein kinase II contributes to intracellular pH recovery from acidosis via Na(+)/H(+) exchanger activation.
2010,
Pubmed
Warren,
Highly efficient reprogramming to pluripotency and directed differentiation of human cells with synthetic modified mRNA.
2010,
Pubmed
Ybe,
Clathrin self-assembly is regulated by three light-chain residues controlling the formation of critical salt bridges.
1998,
Pubmed
Zhan,
NMDA induces a biphasic change in intracellular pH in rat hippocampal slices.
1997,
Pubmed
Zhang,
Vesicular ATPase inserted into the plasma membrane of motor terminals by exocytosis alkalinizes cytosolic pH and facilitates endocytosis.
2010,
Pubmed
