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| Open AccessThe sulfite oxidase Shopper controls neuronal activity by regulating glutamate homeostasis in Drosophila ensheathing glia
In Drosophila, ensheathing glia encase the neuropil but their function is not well understood. Here the authors show a surprising role of ensheathing glia in regulating glutamate homeostasis and locomotion which is controlled by the sulfite oxidase Shopper.
- Nils Otto
- , Zvonimir Marelja
- & Christian Klämbt
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Article
| Open AccessVti1a/b regulate synaptic vesicle and dense core vesicle secretion via protein sorting at the Golgi
Vti1a and Vti1b are SNARE proteins implicated in regulated secretion. Here the authors show that Vti1a and Vti1b control protein sorting at the Golgi, and targeting to the axon, and thereby indirectly control regulated secretion at the synapse.
- Javier Emperador-Melero
- , Vincent Huson
- & Matthijs Verhage
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| Open AccessSimultaneous dendritic voltage and calcium imaging and somatic recording from Purkinje neurons in awake mice
Dendritic integration is important for information processing in the brain. Here, in awake mice, authors combine simultaneous dendritic recording of voltage and calcium signals, with somatic recording from Purkinje neurons, enabling characterization of dendritic spiking, action potential backpropagation, and ‘hotspots’ in spiny dendrites.
- Christopher J. Roome
- & Bernd Kuhn
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Article
| Open AccessDevelopmental seizures and mortality result from reducing GABAA receptor α2-subunit interaction with collybistin
The inhibitory synaptic protein collybistin (CB) and GABAAR-α subunits are thought to interact, but strength and specificity are unclear. Here the authors study the CB–α2 interaction and show that a mouse mutated in the CB-binding region of α2 displays a loss of specific synapses and seizure.
- Rochelle M. Hines
- , Hans Michael Maric
- & Stephen J. Moss
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| Open AccessCo-transmission of acetylcholine and GABA regulates hippocampal states
Acetylcholine (ACh) release in the central nervous system is thought to be unitary and mediated non-synaptically in volume transmission. Here, Takács and colleagues show cholinergic terminals juxtapose GABAergic synapses anatomically and functionally, and GABA and ACh molecules are co-transmitted.
- Virág T. Takács
- , Csaba Cserép
- & Gábor Nyiri
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| Open AccessDesigning a norepinephrine optical tracer for imaging individual noradrenergic synapses and their activity in vivo
The noradrenergic system plays numerous physiological roles but tools to study it are scarce. Here the authors develop a fluorescent analogue of norepinephrine that can be used to label noradrenergic neurons and the synaptic vesicles, and use it to measure single synaptic vesicle release sites in living mice.
- Matthew Dunn
- , Adam Henke
- & Dalibor Sames
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Article
| Open AccessPostsynaptic RIM1 modulates synaptic function by facilitating membrane delivery of recycling NMDARs in hippocampal neurons
Rab3-interacting molecules (RIMs) are a key component of the presynaptic active zone that regulate neurotransmitter release. Here, the authors show that RIM1 also has postsynaptic function to organize NMDA receptors and synaptic response.
- Jiejie Wang
- , Xinyou Lv
- & Shuang Qiu
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Article
| Open AccessSingle synaptic inputs drive high-precision action potentials in parvalbumin expressing GABA-ergic cortical neurons in vivo
In superficial layers of the cortex, excitatory neurons often fire single action potentials. Here, using multiple whole-cell recordings in vivo, the authors show that single excitatory synaptic events can drive GABA-ergic parvalbumin neurons to fire, triggering inhibition of other pyramidal neurons.
- Jean-Sébastien Jouhanneau
- , Jens Kremkow
- & James F. A. Poulet
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Article
| Open AccessSynaptically silent sensory hair cells in zebrafish are recruited after damage
Hair cells of the inner ear are mechanosensors that detect sound, and synapse onto afferent neurons. Here, the authors used calcium imaging to find that not all hair cells are synaptically engaged, but after damage these silent cells are synaptically engaged.
- Qiuxiang Zhang
- , Suna Li
- & Katie S. Kindt
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Article
| Open AccessAlcohol exposure disrupts mu opioid receptor-mediated long-term depression at insular cortex inputs to dorsolateral striatum
µ-opioid receptors (MOR) are known to modulate the reward effects of drugs of abuse, and MOR activation induces long-term depression (LTD) at striatal synapses. Here the authors show that alcohol exposure disrupts MOR-induced LTD only at specific cortical inputs to the striatum.
- Braulio Muñoz
- , Brandon M. Fritz
- & Brady K. Atwood
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Article
| Open AccessMembrane cholesterol mediates the cellular effects of monolayer graphene substrates
Understanding the biological role of graphene in eukaryotic cells is essential for future biomedicine applications. Here, the authors investigate the interaction of neurons and fibroblasts with graphene substrates, which increase cell membrane cholesterol and potentiate neurotransmitter release and receptor signaling.
- Kristina E. Kitko
- , Tu Hong
- & Qi Zhang
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Article
| Open AccessQuantitative optical nanophysiology of Ca2+ signaling at inner hair cell active zones
Quantitatively studying components of the presynapse requires high resolution optical methods. Here the authors use confocal microscopy as well as 2D- and 3D-STED nanoscopy to quantify the number and activity of active zone Ca2+ channels in inner hair cells.
- Jakob Neef
- , Nicolai T. Urban
- & Tobias Moser
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Article
| Open AccessDysbindin links presynaptic proteasome function to homeostatic recruitment of low release probability vesicles
At the fly neuromuscular junction, postsynaptic receptor perturbation induces homeostatic enhancement of neurotransmitter release. Here, the authors show that the presynaptic proteasome controls a vesicle pool required for homeostatic plasticity and that dysbindin is required to access this pool.
- Corinna Wentzel
- , Igor Delvendahl
- & Martin Müller
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Article
| Open AccessVGLUT1 functions as a glutamate/proton exchanger with chloride channel activity in hippocampal glutamatergic synapses
During neurotransmission synaptic vesicles are filled with glutamate by vesicular glutamate transporters (VGLUTs). Here, authors image intact neurons and show that in synaptic vesicles VGLUT functions as a glutamate/proton exchanger associated with a channel-like chloride conductance.
- Magalie Martineau
- , Raul E. Guzman
- & Jürgen Klingauf
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Article
| Open AccessElectrical synapses convey orientation selectivity in the mouse retina
Visual input received by photoreceptors is relayed to retinal ganglion cells (RGCs), which have selectivity for inputs of certain orientations. Here, the authors show that gap junction-mediated input onto one type of RGC contributes to its orientation selectivity.
- Amurta Nath
- & Gregory W. Schwartz
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Article
| Open AccessDynamic disorganization of synaptic NMDA receptors triggered by autoantibodies from psychotic patients
Autoantibodies are found in neuropsychiatric conditions but without clear cellular mechanism and disease relevance. This study shows higher prevalence of autoantibodies against NMDAR receptors in schizophrenia patients, and patient-associated antibody can alter synaptic receptor trafficking and plasticity.
- Julie Jézéquel
- , Emily M. Johansson
- & Laurent Groc
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Article
| Open AccessGABAA receptor dependent synaptic inhibition rapidly tunes KCC2 activity via the Cl−-sensitive WNK1 kinase
GABAergic transmission regulates the K+-Cl− co-transporter KCC2. Here the authors demonstrate that inhibitory transmission, via GABAA receptor and WNK signaling, regulates KCC2 expression in the membrane of hippocampal neurons.
- Martin Heubl
- , Jinwei Zhang
- & Sabine Lévi
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Article
| Open AccessSemisynthetic fluorescent pH sensors for imaging exocytosis and endocytosis
Existing pH-sensitive red fluorescent protein probes don’t perform well in monitoring exocytosis and endocytosis. Here, the authors combine organic dyes with self-labeling tags or antibodies to develop semisynthetic protein conjugates that can image synaptic vesicle fusion events in living cells.
- Magalie Martineau
- , Agila Somasundaram
- & David Perrais
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Article
| Open AccessAIP limits neurotransmitter release by inhibiting calcium bursts from the ryanodine receptor
In this work the authors show that AIP (aryl hydrocarbon receptor-interacting protein), a gene frequently mutated in association with pituitary tumors, regulates neurotransmitter release by inhibiting calcium release from ryanodine receptors.
- Bojun Chen
- , Ping Liu
- & Zhao-Wen Wang
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| Open AccessIn vivo neurochemical measurements in cerebral tissues using a droplet-based monitoring system
Current approaches studying the collection of extracellular fluid to monitor neurological disorders have temporal resolution limitations. Here the authors show functional in vivo validation of a droplet collection system included at the tip of a neural probe.
- Guillaume Petit-Pierre
- , Philippe Colin
- & Philippe Renaud
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| Open AccessFunctional mapping of brain synapses by the enriching activity-marker SynaptoZip
Visualization of synaptic activity in the living brain is challenging. This study devises a simple and efficient scheme that reports synaptic vesicle recycling in vivo using SynaptoZip, a genetically encoded sensor of past synaptic activities.
- Mattia Ferro
- , Jacopo Lamanna
- & Antonio Malgaroli
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| Open AccessExtrapyramidal side effects of antipsychotics are linked to their association kinetics at dopamine D2 receptors
Atypical antipsychotics show reduced extrapyramidal side effects compared to first generation drugs. Here the authors use time-resolved FRET to measure binding kinetics, and show that side effects correlate with drug association rates to the D2 receptor, while dissociation rates correlate with prolactin elevation.
- David A. Sykes
- , Holly Moore
- & Steven J. Charlton
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| Open AccessDistance-dependent inhibition facilitates focality of gamma oscillations in the dentate gyrus
Perisomatic-inhibitory interneurons (PIIs) contribute to the generation of gamma oscillations in the hippocampus. Here the authors demonstrate distance-dependent inhibition between PIIs in freely moving mice, and use computational analysis to show that distance-dependent inhibition supports the emergence of focal gamma bursts.
- Michael Strüber
- , Jonas-Frederic Sauer
- & Marlene Bartos
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Article
| Open AccessAn autism spectrum disorder-related de novo mutation hotspot discovered in the GEF1 domain of Trio
Trio is a RhoGEF protein that promotes actin polymerization and is implicated in the regulation of glutamatergic synapses in autism spectrum disorder (ASD). Here the authors identify a large cluster of de novo mutations in the GEF1 domain of Trio in whole-exome sequencing data from individuals with ASD, and confirm that some of these mutations lead to glutamatergic dysregulation in vitro.
- Anastasiia Sadybekov
- , Chen Tian
- & Bruce E. Herring
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| Open AccessMunc13-1 and Munc18-1 together prevent NSF-dependent de-priming of synaptic vesicles
The molecular mechanism underlying the generation and maintenance of the readily releasable pool composed of primed synaptic vesicles is only partially known. Here the authors show that in mouse primary neurons, Munc13-1 and Munc18-1 stabilize primed synaptic vesicles by preventing NSF-dependent de-priming.
- Enqi He
- , Keimpe Wierda
- & Matthijs Verhage
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Article
| Open AccessTau association with synaptic vesicles causes presynaptic dysfunction
Mislocalisation of tau occurs in several neurodegenerative diseases and is thought to contribute to synaptic function. The authors show that presynaptically, tau binds to synaptic vesicles via the N-terminus which contributes to synaptic dysfunction.
- Lujia Zhou
- , Joseph McInnes
- & Patrik Verstreken
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Article
| Open AccessHeterodimerization of Munc13 C2A domain with RIM regulates synaptic vesicle docking and priming
The interaction between RIM and the C2A domain of Munc13 is known to be required for synaptic vesicle priming. Here the authors show new implications of the C2A domain of Munc13, through its dynamic interaction with RIM, in orchestrating a wide range of modulatory operations that shape vesicle docking, priming and neurotransmitter release.
- Marcial Camacho
- , Jayeeta Basu
- & Christian Rosenmund
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Article
| Open AccessTRPV1 channels are critical brain inflammation detectors and neuropathic pain biomarkers in mice
TRPV1 is known to be expressed in peripheral structures and the spinal cord, especially for pain processing. Here the authors show that in the brain, in particular the anterior cingulate cortex, TRPV1 is functionally expressed in microglia; stimulation of TRPV1 activates microglia, which in turn affects glutamatergic neurotransmission.
- Maria Cristina Marrone
- , Annunziato Morabito
- & Silvia Marinelli
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| Open AccessNeurons and neuronal activity control gene expression in astrocytes to regulate their development and metabolism
How neurons and neuronal activity regulate astrocyte functions is poorly understood. Haselet al. identify two large groups of astrocytic genes that are regulated by neuronal contact and synaptic activity respectively, with distinct roles in astrocytic function; interestingly, many of these genes are dysregulated in neurodegeneration.
- Philip Hasel
- , Owen Dando
- & Giles E. Hardingham
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| Open AccessAntidromic-rectifying gap junctions amplify chemical transmission at functionally mixed electrical-chemical synapses
Emerging evidence suggests that chemical and electrical synapses interact to regulate the strength of synaptic transmission. Liuet al. report that in a C. elegansescape circuit, functionally mixed electrical-chemical synapses exist between premotor interneurons and downstream motor neurons, and that the electrical synapse amplifies the chemical transmission between the neurons.
- Ping Liu
- , Bojun Chen
- & Zhao-Wen Wang
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| Open AccessEpilepsy and intellectual disability linked protein Shrm4 interaction with GABABRs shapes inhibitory neurotransmission
Mutations in the gene encoding Shrm4 are associated with epilepsy and intellectual disability. The authors show that Shrm4 interacts with GABABreceptors and regulates tonic inhibition in the hippocampus, and knockdown of Shrm4 in rats leads to anxiety-like behaviour and seizures.
- Jonathan Zapata
- , Edoardo Moretto
- & Maria Passafaro
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Article
| Open AccessNMDA-receptor-dependent plasticity in the bed nucleus of the stria terminalis triggers long-term anxiolysis
The bed nucleus of the stria terminalis (BNST) is known to modulate anxiety-related behaviours. Here the authors show that excitatory inputs from infralimbic cortex and ventral subiculum/CA1 converge onto the same BNST neurons; stimulation of vSUB/CA1 triggers LTP in BNST and reduces anxiety in rats.
- Christelle Glangetas
- , Léma Massi
- & François Georges
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Article
| Open AccessSelective molecular impairment of spontaneous neurotransmission modulates synaptic efficacy
Emerging evidence suggests that spontaneous neurotransmitter release contributes to the maintenance of synaptic efficacy. Here the authors selectively reduce spontaneous glutamatergic transmission while leaving the stimulus-evoked responses intact and show that this leads to homeostatic scaling at the postsynaptic side in cultured neurons and alters synaptic plasticity in acute brain slices.
- Devon C. Crawford
- , Denise M. O. Ramirez
- & Ege T. Kavalali
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| Open AccessIn vivo single-molecule imaging of syntaxin1A reveals polyphosphoinositide- and activity-dependent trapping in presynaptic nanoclusters
Syntaxin1A (Sx1A) is organized in nanoclusters in neurosecretory cells but how these nanoclusters are affected by neurotransmitter release in a living organism is unknown. Here the authors perform single molecule imaging analysis in live fly larvae and show that the lateral diffusion and trapping of Sx1A in nanoclusters are altered by synaptic activity.
- Adekunle T. Bademosi
- , Elsa Lauwers
- & Frédéric A. Meunier
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| Open AccessAtomic structure of the innexin-6 gap junction channel determined by cryo-EM
Gap junctions have critical roles in maintaining homeostasis in multicellular organisms. Here the authors present cryo-EM structures of the C. elegansinnexin-6 gap junction channel, revealing high structural similarity to human connexin 26 despite a different oligomeric number and lack of sequence similarity.
- Atsunori Oshima
- , Kazutoshi Tani
- & Yoshinori Fujiyoshi
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Article
| Open AccessAstrocytic GABA transporter activity modulates excitatory neurotransmission
Astrocytes monitor and regulate both excitatory and inhibitory synaptic activity. Here, the authors identify a novel form of neuronal-glia communication, by which astrocytes detect rises in GABA via the GABA transporter GAT-3; this results in adenosine release that acts presynaptically to inhibit neural glutamatergic signalling.
- Kim Boddum
- , Thomas P. Jensen
- & Matthew C. Walker
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Article
| Open AccessDendritic NMDA spikes are necessary for timing-dependent associative LTP in CA3 pyramidal cells
Back-propagating action potentials (bAP) and NMDA dendritic spikes have both been linked to long-term plasticity (LTP) induction, though it is unclear which factors are essential. Here, using electrophysiology and Ca2+imaging, the authors find NMDA spikes are a key initiator of LTP, and that bAP contribution occurs via NMDA spike triggering.
- Federico Brandalise
- , Stefano Carta
- & Urs Gerber
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Article
| Open AccessMolecular determinants for the strictly compartmentalized expression of kainate receptors in CA3 pyramidal cells
Kainate receptors are selectively found at CA3-mossy fibre synapses, although the mechanisms regulating this compartmentalisation have yet to be determined. Here, the authors find KAR segregation is dependent on the amount of GluK2a protein and an interaction between the GluK2 C-terminal domain and N-cadherin.
- Sabine Fièvre
- , Mario Carta
- & Christophe Mulle
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Article
| Open AccessTransport of a kinesin-cargo pair along microtubules into dendritic spines undergoing synaptic plasticity
Transport of cargo into dendritic spines is required for synaptic plasticity. McVicker et al.describe a method of activity-dependent transport of a kinesin KIF1A and its cargo synaptotagmin-IV along microtubules that are transiently polymerized into dendritic spines.
- Derrick P. McVicker
- , Adam M. Awe
- & Erik W. Dent
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Article
| Open AccessStructural basis of synaptic vesicle assembly promoted by α-synuclein
α-synuclein, a protein associated to Parkinson's disease, is involved in synaptic vesicle interaction and assembly. Here, the authors use NMR spectroscopy and super-resolution microscopy to unveil the nature and molecular mechanism of α-synuclein-mediated synaptic vesicle clustering.
- Giuliana Fusco
- , Tillmann Pape
- & Alfonso De Simone
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Article
| Open AccessActin dynamics provides membrane tension to merge fusing vesicles into the plasma membrane
As vesicles fuse to the plasma membrane, they form intermediate Ω-shaped structures followed by either closure of the pore or full merging with the plasma membrane. Here Wen et al. show that dynamic actin assembly provides membrane tension to promote Ω merging in neuroendocrine cells and synapses.
- Peter J. Wen
- , Staffan Grenklo
- & Ling-Gang Wu
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Article
| Open AccessSALM4 suppresses excitatory synapse development by cis-inhibiting trans-synaptic SALM3–LAR adhesion
Synaptic adhesion molecules regulate synapse development and function by both cis and trans-interactions. Here, Lie et al. show that postsynaptic SALM4 regulates excitatory synapse numbers by cisinhibition of the SALM3-LAR transynaptic interaction.
- Eunkyung Lie
- , Ji Seung Ko
- & Eunjoon Kim
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Article
| Open AccessOrexins contribute to restraint stress-induced cocaine relapse by endocannabinoid-mediated disinhibition of dopaminergic neurons
Stress is a major cause of relapse to cocaine seeking behaviour. Tung et al. show that orexin mediates stress-induced reinstatement of cocaine seeking behaviour in mice by endocannabinoid-dependent disinhibition in the ventral tegmental area.
- Li-Wei Tung
- , Guan-Ling Lu
- & Lih-Chu Chiou
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Article
| Open AccessHuman NK cell development requires CD56-mediated motility and formation of the developmental synapse
CD56, a splicing variant of NCAM, marks human NK cell differentiation stages. Here the authors show that developing human NK cells form CD56-enriched synapses with stromal cells, and CD56 is critical to promote motility of NK cells that increases with their maturation.
- Emily M. Mace
- , Justin T. Gunesch
- & Jordan S. Orange
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Article
| Open AccessLRRK2 regulates retrograde synaptic compensation at the Drosophila neuromuscular junction
Mutations in the protein LRRK2 have been associated with Parkinson's disease but little is still known about the basic functions of the protein in the brain. Here the authors show that in fruit flies, LRRK2 regulates retrograde homeostatic synaptic compensation at the larval neuromuscular junction.
- Jay Penney
- , Kazuya Tsurudome
- & A. Pejmun Haghighi
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Article
| Open AccessActivation of D2 dopamine receptor-expressing neurons in the nucleus accumbens increases motivation
Striatal D1 and D2-receptor expressing neurons have been shown to have opposing effects on reward-related behaviours. Here the authors reveal that specific activation of both D1 and D2 neurons in the nucleus accumbens leads to increase in motivational drive in rodents.
- Carina Soares-Cunha
- , Barbara Coimbra
- & Ana J. Rodrigues
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Article
| Open AccessLRP6 acts as a scaffold protein in cardiac gap junction assembly
LRP6 is known for its role as a Wnt co-receptor essential for the canonical Wnt/β-catenin signaling. Here, Li et al. show that LRP6 exerts a Wnt-independent scaffold function and regulates connexin 43 gap junction formation and coupling of cardiomyocytes in mouse hearts.
- Jun Li
- , Changming Li
- & Yi-Han Chen
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Article
| Open AccessBidirectional regulation of synaptic transmission by BRAG1/IQSEC2 and its requirement in long-term depression
BRAG1 mutations are linked to synaptic deficits and X-chromosome linked intellectual disability. Here, the authors show that BRAG1 mediates activity-dependent removal of synaptic AMPA receptors via Arf-GEF activity and PDZ interactions, and is required for maintaining AMPAR-mediated synaptic transmission.
- Joshua C. Brown
- , Amber Petersen
- & Nashaat Z. Gerges
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Article
| Open AccessDifferent states of synaptotagmin regulate evoked versus spontaneous release
Synaptotagmin contains tandem Ca2+-binding C2-domains that interact with target membranes to trigger exocytosis. Here, Bai et al. manipulate the relative orientation of these two domains using a synthetic polyproline linker and show that a parallel orientation is most effective for membrane interaction and exocytosis.
- Hua Bai
- , Renhao Xue
- & Edwin R. Chapman