MCTP is an ER-resident calcium sensor that stabilizes synaptic transmission and homeostatic plasticity

Genç, Özgür; Dickman, Dion; Ma, Wenpei; Tong, Amy; Fetter, Richard D.; Davis, Graeme W.

doi:10.7554/elife.22904

Cited by 48 publications

(55 citation statements)

References 69 publications

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“…4A). MCTP2 is an 878 amino acid ER resident protein with a membrane embedded regions containing the RHD near the Cterminus and three C2 domains 27,28 . MCTP proteins are conserved in higher eukaryotes.…”

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confidence: 99%

Lipid droplet and peroxisome biogenesis occur at the same ER subdomains

Joshi

Choudhary

Levine

et al. 2017

Preprint

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Nascent lipid droplet (LD) formation occurs in the ER membrane 1-4 . It is not knownwhether LD biogenesis occurs stochastically in the ER or at subdomains with unique protein and lipid composition. We previously identified ER subdomains in S. cerevisiae that contain Pex30, a reticulon-like ER-resident membrane protein 5 . There are ~25 Pex30-containing puncta in the ER per cell. These sites are regions where preperoxisomal vesicles (PPVs) are generated 5 . Here we show that Pex30 subdomains are also the location where most nascent LDs form. Mature LDs remain associated with Pex30 subdomains and the same Pex30 subdomain can simultaneously associate with a LD and a PPV. Pex30 subdomains become highly enriched in diacylglycerol (DAG) during LD biogenesis, indicating they have a unique lipid composition. We find that in higher eukaryotes multiple C2 domain containing transmembrane protein (MCTP2) is the functional homologue of Pex30; MCTP2 resides in ER subdomains where most nascent LD biogenesis occurs and that are often associated with peroxisomes. Together, these findings indicate that most LDs and PPVs form and remain associated with conserved ER subdomains and suggest a link between LD and peroxisome biogenesis.LDs are composed of a core of neutral lipids, triacylglycerides (TAG) and sterol esters, covered by a phospholipid monolayer containing proteins. LD biogenesis probably begins when neutral lipids in the ER coalesce to form lens-like structures between the leaflets of the membrane 6 . These lenses subsequently grow larger and bud from the ER, forming mature LDs 7-10 . How locations of LD biogenesis in the ER membrane are determined is not known but there is evidence that biogenesis might occur at specialized sites 1, 4 . A) Images of pex3atg1D cells expressing endogenously tagged Pex30-2xmCherry, Pex14-YFP (a PPV maker), and Erg6-BFP (an LD marker) from plasmids. Stacks of 3 images with a step size of 0.25µm were taken and deconvolved; images from single plane are shown. Bar = 3µm. B) Images of COS7 cells transiently co-transfected with plasmids expressing YFP-MCTP2, LiveDrop-mCherry (an LD marker), CFP-SKL (a peroxisome marker). Stacks of 20 images with a step size of 0.3µm were taken and deconvolved; images from single plane are shown. Bar = 5 µm. C) Quantification of percent colocalization of punctae from (B), n =300 punctae. Supplement figure 1. Data associated with Fig. 1. A) Same as Fig. 1A except that LDs are visualized using BODIPY instead of Erg6-GFP. Bar = 3µm. B) Same as Fig. 1C except cells are expressing endogenously tagged Pex30-2xmCherry and Lro1-GFP from a plasmid. Bar = 3µm. C) Images of cells expressing endogenously tagged ss-RFP-HDEL (an ER maker) and ER-DAG sensor from a plasmid. D) The C-terminal 273 amino acids of Pex30 fused to MBP were purified from E.coli.The purified was protein (0.5µg/ml) was incubated with a lipid strip (Echelon Inc., catalog # P-6002) for 1 hour at room temperature. The lipid strip was immunoblotted with anti-MBP antibody. Fig. 2. Supplement figure 2. Data ass...

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confidence: 99%

Lipid droplet and peroxisome biogenesis occur at the same ER subdomains

Joshi

Choudhary

Levine

et al. 2017

Preprint

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“…The majority of recent studies about synaptic homeostasis at the Drosophila NMJ have emphasized that presynaptic adjustments to neurotransmitter release properties must occur within minutes of drug-induced (PhTox) postsynaptic receptor inhibition in order to induce a rapid and offsetting response to PhTox challenge. Important presynaptic parameters uncovered through these studies include regulation of presynaptic Ca 2+ influx (Frank et al, 2006; Frank et al, 2009; Müller and Davis, 2012; Wang et al, 2014; Wang et al, 2016a; Younger et al, 2013); regulation of the size of the readily releasable pool (RRP) of presynaptic vesicles (Harris et al, 2015; Müller et al, 2015; Müller et al, 2012; Wang et al, 2016a; Weyhersmüller et al, 2011); control of SNARE-mediated fusion events (Dickman and Davis, 2009; Dickman et al, 2012; Müller et al, 2011); control of neuronal excitability (Bergquist et al, 2010; Parrish et al, 2014; Younger et al, 2013); and recently, ER calcium-sensing downstream of presynaptic calcium influx (Genç et al, 2017). For almost all of the cases in which a mutation or an experimental condition blocks the short-term induction of homeostatic signaling, the same perturbation has also proven to block its long-term maintenance.…”

Section: Discussionmentioning

confidence: 99%

Synaptic homeostasis at the Drosophila neuromuscular junction is a reversible signaling process that is sensitive to high temperature

Yeates

Frank

2017

Preprint

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3Homeostasis is a vital mode of biological self-regulation. The hallmarks of homeostasis 2 4 3 1 sophila melanogaster neuromuscular junction (NMJ). At the Drosophila NMJ, impairment of glu-3 2 tamate receptors causes a decrease in quantal size, which is offset by a corrective, homeostatic 3 3increase in the number of vesicles released per evoked presynaptic stimulus, or quantal con-3 4 tent. This process has been termed presynaptic homeostatic potentiation (PHP). Taking ad-3 5 vantage of a GAL4/GAL80 TS /UAS expression system, we triggered PHP by expressing a domi-3 6 nant-negative glutamate receptor subunit at the NMJ. We then reversed PHP by halting expres-3 7 sion of the dominant-negative receptor. Our data show that PHP is fully reversible over a time 3 8 course of 48-72 hours after the dominant-negative glutamate receptor stops being genetically 3 9expressed. Additionally, we found that the PHP response triggered by the dominant-negative 4 0 subunit was ablated at high temperatures. Our data show that the long-term maintenance of 4 1 PHP at the Drosophila NMJ is a reversible regulatory process that is sensitive to temperature. 4 2 4 3 SIGNIFICANCE STATEMENT 4 4

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“…Specifically, it was found that release at NMJs undergoing PHP is more sensitive to EGTA-AM, and that EGTA-sensitive vesicles are required for PHP (Wentzel et al, 2018) (but see Genç et al, 2017). This implies that loosely coupled vesicles have to be recruited in addition to tightly coupled vesicles to potentiate release during PHP (see also paragraph "Proteostasis").…”

Section: Physiology and Genesmentioning

confidence: 99%

Homeostatic control of Drosophila neuromuscular junction function

Frank

James

Müller

2019

Synapse

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The ability to adapt to changing internal and external conditions is a key feature of biological systems. Homeostasis refers to a regulatory process that stabilizes dynamic systems to counteract perturbations. In the nervous system, homeostatic mechanisms control neuronal excitability, neurotransmitter release, neurotransmitter receptors, and neural circuit function. The neuromuscular junction (NMJ) of Drosophila melanogaster has provided a wealth of molecular information about how synapses implement homeostatic forms of synaptic plasticity, with a focus on the transsynaptic, homeostatic modulation of neurotransmitter release. This review examines some of the recent findings from the Drosophila NMJ and highlights questions the field will ponder in coming years.

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MCTP is an ER-resident calcium sensor that stabilizes synaptic transmission and homeostatic plasticity

Cited by 48 publications

References 69 publications

Lipid droplet and peroxisome biogenesis occur at the same ER subdomains

Lipid droplet and peroxisome biogenesis occur at the same ER subdomains

Synaptic homeostasis at the Drosophila neuromuscular junction is a reversible signaling process that is sensitive to high temperature

Homeostatic control of Drosophila neuromuscular junction function

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