The membrane domain of vacuolar H+ATPase: a crucial player in neurotransmitter exocytotic release

Morel, Nicolas; Poëa-Guyon, Sandrine

doi:10.1007/s00018-015-1886-2

Cited by 30 publications

(23 citation statements)

References 116 publications

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“…1) if 2-BFI-induced antinociception were mediated through elevated monoamine release. Similarly, Ca 2+ -bound calmodulin is important for vesicle exocytosis (Di Giovanni et al 2010; Morel and Poea-Guyon 2015) and is thought to promote vesicle-SNARE protein binding as well as vesicle pool replenishment (Lipstein et al 2013). Thus, calmodulin inhibition could exert a powerful modulatory effect on a drug target which involves increased levels and release of vesicular monoamines.…”

Section: Discussionmentioning

confidence: 99%

Role of intracellular Ca2+ signaling in the antinociceptive and discriminative stimulus effects of the imidazoline I2 receptor agonist 2-BFI in rats

et al. 2017

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Rationale Recent research has established the imidazoline I2 receptor as a promising target for the development of novel analgesics. However, despite an increasing understanding of imidazoline I2 receptor-mediated behavioral effects, little is known about post-I2-receptor signaling mechanisms. Objective This study examined the effects of several inhibitors of Ca2+ signaling mechanisms on two behavioral effects of the prototypical imidazoline I2 receptor ligand 2-BFI. Methods The von Frey filament test was used to examine the antinociceptive effects of 2-BFI in complete Freund’s adjuvant (CFA)-induced inflammatory pain in rats. A two-lever drug discrimination paradigm in which rats were trained to discriminate 5.6 mg/kg (i.p.) 2-BFI from its vehicle was used to examine the discriminative stimulus effects of 2-BFI. Results The L-type Ca2+ channel blockers verapamil and nimodipine, the calmodulin antagonist W-7, and the internal Ca2+ release inhibitor ryanodine all attenuated the antinociceptive effects of 2-BFI. Oxycodone- and acetaminophen-induced antinociception were unaffected by pretreatment with the Ca2+ channel blockers. Rats learned to reliably discriminate 5.6 mg/kg 2-BFI from saline. The I2 receptor agonists BU224, RS45041, tracizoline, and CR4056 all fully substituted for 5.6 mg/kg 2-BFI while idazoxan, S22687, 2,5-Dimethoxy-4-methylamphetamine (DOM), and phenyzoline produced partial or no substitution. Verapamil, nimodipine, and W-7 did not alter the discriminative stimulus effects of 2-BFI. Conclusion These results indicate that the antinociceptive effects of 2-BFI involve intracellular Ca2+ elevation and/or downstream Ca2+/calmodulin signaling, whereas the discriminative stimulus effects of 2-BFI are mediated by a distinct, independent mechanism.

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Section: Discussionmentioning

confidence: 99%

Role of intracellular Ca2+ signaling in the antinociceptive and discriminative stimulus effects of the imidazoline I2 receptor agonist 2-BFI in rats

et al. 2017

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“…These converging data suggest a role for ATP6AP2 in synaptic vesicle homeostasis, which is in agreement with a close functional relationship of ATP6AP2 with V-ATPase and its role in synaptic vesicle acidification. V-ATPase is required for synaptic vesicles loading with neurotransmitters ( 39 ). In addition, the V0 domain of V-ATPase is part of a complex involved in the fusion of synaptic vesicles with the plasma membrane and thus participates in the regulation of neurotransmitter release ( 40 ).…”

Section: Discussionmentioning

confidence: 99%

Conditional depletion of intellectual disability and Parkinsonism candidate gene ATP6AP2 in fly and mouse induces cognitive impairment and neurodegeneration

Dubos

Castells-Nobau²,

Méziane

et al. 2015

Hum. Mol. Genet.

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ATP6AP2, an essential accessory component of the vacuolar H+ ATPase (V-ATPase), has been associated with intellectual disability (ID) and Parkinsonism. ATP6AP2 has been implicated in several signalling pathways; however, little is known regarding its role in the nervous system. To decipher its function in behaviour and cognition, we generated and characterized conditional knockdowns of ATP6AP2 in the nervous system of Drosophila and mouse models. In Drosophila, ATP6AP2 knockdown induced defective phototaxis and vacuolated photoreceptor neurons and pigment cells when depleted in eyes and altered short- and long-term memory when depleted in the mushroom body. In mouse, conditional Atp6ap2 deletion in glutamatergic neurons (Atp6ap2Camk2aCre/0 mice) caused increased spontaneous locomotor activity and altered fear memory. Both Drosophila ATP6AP2 knockdown and Atp6ap2Camk2aCre/0 mice presented with presynaptic transmission defects, and with an abnormal number and morphology of synapses. In addition, Atp6ap2Camk2aCre/0 mice showed autophagy defects that led to axonal and neuronal degeneration in the cortex and hippocampus. Surprisingly, axon myelination was affected in our mutant mice, and axonal transport alterations were observed in Drosophila. In accordance with the identified phenotypes across species, genome-wide transcriptome profiling of Atp6ap2Camk2aCre/0 mouse hippocampi revealed dysregulation of genes involved in myelination, action potential, membrane-bound vesicles and motor behaviour. In summary, ATP6AP2 disruption in mouse and fly leads to cognitive impairment and neurodegeneration, mimicking aspects of the neuropathology associated with ATP6AP2 mutations in humans. Our results identify ATP6AP2 as an essential gene for the nervous system.

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“…V-ATPase, differs from Na + ,K + -ATPase in the plasma membrane, Ca 2+ -ATPase in the sarcoplasmic reticulum, and F 1 ,F 0 -ATP synthase in mitochondria, in that it does not require a coupled influx of permeant anions [ 19 ]. Sulfhydryl alkylating reagents such as N-ethylmaleimide inhibit the V-ATPase dependent acidification of the endosomal-lysosomal system [ 19 – 21 ] as well as the specific inhibitor Bafilomycin A1 [ 22 , 23 ]. V-ATPase is a unique class of ATPase present throughout the membranes which constrain the endocytic pathway, including the trans golgi network (TGN).…”

Section: A Ph Gradient Established By Vacuolar Atpase and Chloride Chmentioning

confidence: 99%

The endosomal-lysosomal system: from acidification and cargo sorting to neurodegeneration

Dammer

Ren

et al. 2015

Transl Neurodegener

464

400

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The endosomal-lysosomal system is made up of a set of intracellular membranous compartments that dynamically interconvert, which is comprised of early endosomes, recycling endosomes, late endosomes, and the lysosome. In addition, autophagosomes execute autophagy, which delivers intracellular contents to the lysosome. Maturation of endosomes and/or autophagosomes into a lysosome creates an unique acidic environment within the cell for proteolysis and recycling of unneeded cellular components into usable amino acids and other biomolecular building blocks. In the endocytic pathway, gradual maturation of endosomes into a lysosome and acidification of the late endosome are accompanied by vesicle trafficking, protein sorting and targeted degradation of some sorted cargo. Two opposing sorting systems are operating in these processes: the endosomal sorting complex required for transport (ESCRT) supports targeted degradation and the retromer supports retrograde retrieval of certain cargo. The endosomal-lysosomal system is emerging as a central player in a host of neurodegenerative diseases, demonstrating potential roles which are likely to be revealed in pathogenesis and for viable therapeutic strategies. Here we focus on the physiological process of endosomal-lysosomal maturation, acidification and sorting systems along the endocytic pathway, and further discuss relationships between abnormalities in the endosomal-lysosomal system and neurodegenerative diseases, especially Alzheimer’s disease (AD).

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The membrane domain of vacuolar H+ATPase: a crucial player in neurotransmitter exocytotic release

Cited by 30 publications

References 116 publications

Role of intracellular Ca2+ signaling in the antinociceptive and discriminative stimulus effects of the imidazoline I2 receptor agonist 2-BFI in rats

Role of intracellular Ca2+ signaling in the antinociceptive and discriminative stimulus effects of the imidazoline I2 receptor agonist 2-BFI in rats

Conditional depletion of intellectual disability and Parkinsonism candidate gene ATP6AP2 in fly and mouse induces cognitive impairment and neurodegeneration

The endosomal-lysosomal system: from acidification and cargo sorting to neurodegeneration

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