Regulation of synaptic vesicle acidification at the neuronal synapse

Gowrisankaran, Sindhuja; Milošević, Ira

doi:10.1002/iub.2235

Cited by 32 publications

(24 citation statements)

References 81 publications

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“…Thus, a synaptic V-ATPase regulator could be devoted to synaptic vesicles as it could be affecting more generally all synaptic V-ATPase complexes, indifferently of their membrane localization. The answer to such questions could help better understand regulations of synaptic transmission, since synaptic V-ATPase activity is one of the presynaptic modulators of quantal response ( Takamori, 2016 ; Gowrisankaran and Milosevic, 2020 ).…”

Section: Discussionmentioning

confidence: 99%

A Novel Neuron-Specific Regulator of the V-ATPase inDrosophila

Dulac

Issa

Sun

et al. 2021

eNeuro

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The V-ATPase is a highly conserved enzymatic complex that ensures appropriate levels of organelle acidification in virtually all eukaryotic cells. While the general mechanisms of this proton pump have been well studied, little is known about the specific regulations of neuronal V-ATPase. Here, we studied CG31030, a previously uncharacterized Drosophila protein predicted from its sequence homology to be part of the V-ATPase family. In contrast to its ortholog ATP6AP1/VhaAC45 which is ubiquitous, we observed that CG31030 expression is apparently restricted to all neurons, and using CRISPR/Cas9-mediated gene tagging, that it is mainly addressed to synaptic terminals. In addition, we observed that CG31030 is essential for fly survival and that this protein co-immunoprecipitates with identified V-ATPase subunits, and in particular ATP6AP2. Using a genetically-encoded pH probe (VMAT-pHluorin) and electrophysiological recordings at the larval neuromuscular junction, we show that CG31030 knockdown induces a major defect in synaptic vesicle acidification and a decrease in quantal size, which is the amplitude of the postsynaptic response to the release of a single synaptic vesicle.These defects were associated with severe locomotor impairments. Overall, our data indicate that CG31030, which we renamed VhaAC45-related protein (VhaAC45RP), is a specific regulator of neuronal V-ATPase in Drosophila that is required for proper synaptic vesicle acidification and neurotransmitter release.

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Section: Discussionmentioning

confidence: 99%

A Novel Neuron-Specific Regulator of the V-ATPase inDrosophila

Dulac

Issa

Sun

et al. 2021

eNeuro

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“…For instance, the murine ASIC1 is activated by protonergic neurotransmission, which might constitute a short increase in acidification due to neurotransmission, but could also represent a highly variable acidic environment depending on the rate of exocytosis (Du et al, 2014). Protons are co-packed in presynaptic vesicles with other neurotransmitters by the action of the proton pump Vacuolar-type ATPase (V-ATPase) (Gowrisankaran & Milosevic, 2020), and then co-released into the synaptic cleft, inducing a brief local drop in pH of 0.2 to 0.6 units (Miesenbock et al ., 1998; Du et al ., 2014; Zeng et al ., 2015). This in turn stimulates postsynaptic receptors such as the ASICs (Soto et al ., 2018).…”

Section: Discussionmentioning

confidence: 99%

Physiological insight into the conserved properties ofCaenorhabditis elegansacid-sensing DEG/ENaCs

Kaulich

McCubbin

Schafer

et al. 2022

Preprint

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Acid sensing ion channels (ASICs) are members of the diverse family of degenerin/epithelial sodium channels (DEG/ENaCs). They perform a wide range of physiological roles in healthy organisms, including in gut function and synaptic transmission, but also play important roles in disease, as acidosis is a hallmark of painful inflammatory and ischaemic conditions. We performed a screen for acid-sensitivity on all 30 subunits of the C. elegans DEG/ENaC family using Two-Electrode Voltage Clamp (TEVC) in Xenopus oocytes. We found two groups of acid-sensing DEG/ENaCs characterised by being inhibited or activated by increasing proton concentrations. Three of these acid-sensitive C. elegans DEG/ENaCs were activated by acidic pH, making them functionally similar to the vertebrate ASICs. We also identified four new members of the acid-inhibited DEG/ENaC group, giving a total of seven additional acid-sensitive channels. We observed sensitivity to the anti-hypertensive drug amiloride as well as modulation by the trace element zinc. Acid-sensitive DEG/ENaCs were found to be expressed in both neurons and non-neuronal tissue, highlighting the likely functional diversity of these channels. Our findings provide a framework to exploit the C. elegans channels as models to study the function of these acid-sensing channels in vivo, as well as to study them as potential targets for anti-helminthic drugs.

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“…3b, c, Extended data Fig. 13b, Extended data Table 2), processes required for synapse development, function or both [33][34][35][36] . Importantly, they have low cell-type variability scores, and are thus likely regulated by the Ecdysone-pathway across neuron-types (Fig.…”

Section: The Ecr Cascade Regulates Pan-neuronal and Cell-type Specific Genesmentioning

confidence: 99%

A global timing mechanism regulates cell-type specific wiring programs

Jain

Lin

Kurmangaliyev

et al. 2020

Preprint

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Wiring a complex brain relies on cell-type and temporal-specific expression of genes encoding cell recognition molecules regulating circuit formation1–3. Though genetic programs driving cell-type specificity have been described4–6, how precise temporal control is achieved remains unknown. Here, we describe a global program for the temporal regulation of cell-type-specific wiring genes in the Drosophila visual system. We show that the Ecdysone Receptor induces a synchronous cascade of transcription factors in neurons throughout the visual system in a highly stereotyped fashion. Single-cell RNA-seq analysis of neurons lacking transcription factors in the cascade revealed that targets are cell-type dependent and these are enriched for wiring genes. Knock-down of different transcription factors in this cascade led to defects in sequential steps in wiring. Taken together, this work identifies a synchronous, global program for temporal control of different sets of wiring genes in different neurons. We speculate that this global program coordinates development across cell types to choreograph specific steps in circuit assembly.

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Regulation of synaptic vesicle acidification at the neuronal synapse

Cited by 32 publications

References 81 publications

A Novel Neuron-Specific Regulator of the V-ATPase inDrosophila

A Novel Neuron-Specific Regulator of the V-ATPase inDrosophila

Physiological insight into the conserved properties ofCaenorhabditis elegansacid-sensing DEG/ENaCs

A global timing mechanism regulates cell-type specific wiring programs

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