Proton electrochemical gradient: Driving and regulating neurotransmitter uptake

Farsi, Zohreh; Jahn, Reinhard; Woehler, Andrew

doi:10.1002/bies.201600240

Cited by 29 publications

(29 citation statements)

References 113 publications

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“…8 ), suggesting that the endogenous buffer capacity roughly equals that of a few 10 mM HEPES. This is in line with a recent theoretical estimate of the luminal buffer capacity provided by the ~560 glutamate and ~150 histidine residues in the luminal protein matrix, yielding a buffer capacity of 10–15 mM per pH unit 39 . The impact of high mM of exogenous buffer on the re-acidification rate is confirmed by the use of TRIS as an alternate proton buffer (Supplementary Fig.…”

Section: Resultssupporting

confidence: 90%

VGLUT1 functions as a glutamate/proton exchanger with chloride channel activity in hippocampal glutamatergic synapses

Martineau¹,

Guzman

Fahlke

et al. 2017

Nat Commun

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Glutamate is the major excitatory transmitter in the vertebrate nervous system. To maintain synaptic efficacy, recycling synaptic vesicles (SV) are refilled with glutamate by vesicular glutamate transporters (VGLUTs). The dynamics and mechanism of glutamate uptake in intact neurons are still largely unknown. Here, we show by live-cell imaging with pH- and chloride-sensitive fluorescent probes in cultured hippocampal neurons of wild-type and VGLUT1-deficient mice that in SVs VGLUT functions as a glutamate/proton exchanger associated with a channel-like chloride conductance. After endocytosis most internalized Cl− is substituted by glutamate in an electrically, and presumably osmotically, neutral manner, and this process is driven by both the Cl− gradient itself and the proton motive force provided by the vacuolar H+-ATPase. Our results shed light on the transport mechanism of VGLUT under physiological conditions and provide a framework for how modulation of glutamate transport via Cl− and pH can change synaptic strength.

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Section: Resultssupporting

confidence: 90%

VGLUT1 functions as a glutamate/proton exchanger with chloride channel activity in hippocampal glutamatergic synapses

Martineau¹,

Guzman

Fahlke

et al. 2017

Nat Commun

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“…After endocytosis and vesicle reformation, newly formed SVs must be refilled with neurotransmitter and made fusion-ready (Blakely and Edwards, 2012;Farsi et al, 2017). Regardless of the mechanism of vesicle reformation, each SV must be rapidly loaded with more than a thousand neurotransmitter molecules (Riveros et al, 1986;Burger et al, 1989).…”

Section: Mechanisms Of Sv (Re)acidification and (Re)fillingmentioning

confidence: 99%

The Synaptic Vesicle Cycle Revisited: New Insights into the Modes and Mechanisms

et al. 2019

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Neurotransmission is sustained by endocytosis and refilling of synaptic vesicles (SVs) locally within the presynapse. Until recently, a consensus formed that after exocytosis, SVs are recovered by either fusion pore closure (kiss-and-run) or clathrin-mediated endocytosis directly from the plasma membrane. However, recent data have revealed that SV formation is more complex than previously envisaged. For example, two additional recycling pathways have been discovered, ultrafast endocytosis and activity-dependent bulk endocytosis, in which SVs are regenerated from the internalized membrane and synaptic endosomes. Furthermore, these diverse modes of endocytosis appear to influence both the molecular composition and subsequent physiological role of individual SVs. In addition, previously unknown complexity in SV refilling and reclustering has been revealed. This review presents a modern view of the SV life cycle and discusses how neuronal subtype, physiological temperature, and individual activity patterns can recruit different endocytic modes to generate new SVs and sculpt subsequent presynaptic performance.

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“…Moreover, there is morphological evidence that many presynaptic terminals lack mitochondria (Chavan et al, 2015 ). Accumulation of glutamate into synaptic vesicles depends on the activity of the vacuolar-type H + -ATPase, which drives protons into the lumen by generating a proton electrochemical gradient across the membrane, which drives glutamate into the vesicle (Ikemoto et al, 2003 ; Farsi et al, 2017 ). This has the practical consequence that one ATP is required for each molecule of glutamate accumulated into vesicles instead of the 2 K + taken up and 3 Na + extruded for each molecule ATP used by the Na + , K + -ATPase.…”

Section: Physiological Processes Contributing To Activation-induced Omentioning

confidence: 99%

Integration between Glycolysis and Glutamate-Glutamine Cycle Flux May Explain Preferential Glycolytic Increase during Brain Activation, Requiring Glutamate

Hertz

Chen

2017

Front. Integr. Neurosci.

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The 1988 observation by Fox et al. (1988) that brief intense brain activation increases glycolysis (pyruvate formation from glucose) much more than oxidative metabolism has been abundantly confirmed. Specifically glycolytic increase was unexpected because the amount of ATP it generates is much smaller than that formed by subsequent oxidative metabolism of pyruvate. The present article shows that preferential glycolysis can be explained by metabolic processes associated with activation of the glutamate-glutamine cycle. The flux in this cycle, which is essential for production of transmitter glutamate and GABA, equals 75% of brain glucose utilization and each turn is associated with utilization of ~1 glucose molecule. About one half of the association between cycle flux and glucose metabolism occurs during neuronal conversion of glutamine to glutamate in a process similar to the malate-aspartate shuttle (MAS) except that glutamate is supplied from glutamine, not formed from α-ketoglutarate (αKG) as during operation of conventional MAS. Regular MAS function is triggered by one oxidative process in the cytosol during glycolysis causing NAD+ reduction to NADH. Since NADH cannot cross the mitochondrial membrane (MEM) for oxidation NAD+ is re-generated by conversion of cytosolic oxaloacetate (OAA) to malate, which enters the mitochondria for oxidation and in a cyclic process regenerates cytosolic OAA. Therefore MAS as well as the “pseudo-MAS” necessary for neuronal glutamate formation can only operate together with cytosolic reduction of NAD+ to NADH. The major process causing NAD+ reduction is glycolysis which therefore also must occur during neuronal conversion of glutamine to glutamate and may energize vesicular glutamate uptake which preferentially uses glycolytically derived energy. Another major contributor to the association between glutamate-glutamine cycle and glucose utilization is the need for astrocytic pyruvate to generate glutamate. Although some oxidative metabolism occurs during glutamate formation it is only one half of that during normal tricarboxylic acid (TCA) cycle function. Glutamate’s receptor stimulation leads to potassium ion (K+) release and astrocytic uptake, preferentially fueled by glycolysis and followed by release and neuronal re-accumulation. The activation-induced preferential glycolysis diminishes with continued activation and is followed by an increased ratio between oxidative metabolism and glycolysis, reflecting oxidation of generated glutamate and accumulated lactate.

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Proton electrochemical gradient: Driving and regulating neurotransmitter uptake

Cited by 29 publications

References 113 publications

VGLUT1 functions as a glutamate/proton exchanger with chloride channel activity in hippocampal glutamatergic synapses

VGLUT1 functions as a glutamate/proton exchanger with chloride channel activity in hippocampal glutamatergic synapses

The Synaptic Vesicle Cycle Revisited: New Insights into the Modes and Mechanisms

Integration between Glycolysis and Glutamate-Glutamine Cycle Flux May Explain Preferential Glycolytic Increase during Brain Activation, Requiring Glutamate

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