RIM-Binding Protein, a Central Part of the Active Zone, Is Essential for Neurotransmitter Release

Liu, Karen S. Y.; Siebert, Matthias; Mertel, Sara; Knoche, Elena; Wegener, Stephanie; Wichmann, Carolin; Matkovic, Tanja; Muhammad, Karzan; Depner, Harald; Mettke, Christoph; Bückers, Johanna; Hell, Stefan W.; Müller, Martin; Davis, Graeme W.; Schmitz, Dietmar; Sigrist, Stephan J.

doi:10.1126/science.1212991

Cited by 285 publications

(422 citation statements)

References 39 publications

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“…3a-d). Immunoelectron microscopy revealed the presence of FRa at the surface of exosomes, and two-colour stimulated emission depletion (STED) microscopy 17,18 confirmed the vesicle-specific colocalization of FRa with the exosomal marker Alix (Fig. 3c,d).…”

Section: Localization Of Fra and Pcft In The Human Choroid Plexusmentioning

confidence: 84%

Choroid plexus transcytosis and exosome shuttling deliver folate into brain parenchyma

et al. 2013

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Loss of folate receptor-a function is associated with cerebral folate transport deficiency and childhood-onset neurodegeneration. To clarify the mechanism of cerebral folate transport at the blood-cerebrospinal fluid barrier, we investigate the transport of 5-methyltetrahydrofolate in polarized cells. Here we identify folate receptor-a-positive intralumenal vesicles within multivesicular bodies and demonstrate the directional cotransport of human folate receptora, and labelled folate from the basolateral to the apical membrane in rat choroid plexus cells. Both the apical medium of folate receptor-a-transfected rat choroid plexus cells and human cerebrospinal fluid contain folate receptor-a-positive exosomes. Loss of folate receptor-aexpressing cerebrospinal fluid exosomes correlates with severely reduced 5-methyltetrahydrofolate concentration, corroborating the importance of the folate receptor-a-mediated folate transport in the cerebrospinal fluid. Intraventricular injections of folate receptor-apositive and -negative exosomes into mouse brains demonstrate folate receptor-a-dependent delivery of exosomes into the brain parenchyma. Our results unravel a new pathway of folate receptor-a-dependent exosome-mediated folate delivery into the brain parenchyma and opens new avenues for cerebral drug targeting.

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Section: Localization Of Fra and Pcft In The Human Choroid Plexusmentioning

confidence: 84%

Choroid plexus transcytosis and exosome shuttling deliver folate into brain parenchyma

et al. 2013

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“…Mutants for drbp lack regular T-bars, instead displaying misshapen electron-dense material that is frequently detached from the plasma membrane. Consistent with a severe disruption of the CAZ, drbp mutants have a reduced density of SVs at the plasma membrane, reduced Ca 2+ channel levels, and impairment of evoked release (Liu et al 2011). Syd-1 and Liprin-⍺ localize to the periphery of the CAZ (Fouquet et al 2009;Owald et al 2010).…”

Section: The Active Zone Cytomatrixmentioning

confidence: 91%

“…As characterized by STED microscopy, Drosophila RIM-binding protein (DRBP) forms a ring at the base of the Brp core, where it surrounds a cluster of Ca 2+ channels (Liu et al 2011). Mutants for drbp lack regular T-bars, instead displaying misshapen electron-dense material that is frequently detached from the plasma membrane.…”

Section: The Active Zone Cytomatrixmentioning

confidence: 99%

Transmission, Development, and Plasticity of Synapses

Harris¹,

2015

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Chemical synapses are sites of contact and information transfer between a neuron and its partner cell. Each synapse is a specialized junction, where the presynaptic cell assembles machinery for the release of neurotransmitter, and the postsynaptic cell assembles components to receive and integrate this signal. Synapses also exhibit plasticity, during which synaptic function and/or structure are modified in response to activity. With a robust panel of genetic, imaging, and electrophysiology approaches, and strong evolutionary conservation of molecular components, Drosophila has emerged as an essential model system for investigating the mechanisms underlying synaptic assembly, function, and plasticity. We will discuss techniques for studying synapses in Drosophila, with a focus on the larval neuromuscular junction (NMJ), a well-established model glutamatergic synapse. Vesicle fusion, which underlies synaptic release of neurotransmitters, has been well characterized at this synapse. In addition, studies of synaptic assembly and organization of active zones and postsynaptic densities have revealed pathways that coordinate those events across the synaptic cleft. We will also review modes of synaptic growth and plasticity at the fly NMJ, and discuss how pre-and postsynaptic cells communicate to regulate plasticity in response to activity. KEYWORDS FlyBook; Drosophila; synapse; neurotransmitter release; synaptic plasticity; active zone; synaptic vesicle TABLE OF CONTENTS Abstract 345Introduction 345

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“…Their localization within the active zones of presynaptic nerve terminals (Westenbroek et al 1995) enables the coupling of calcium influx to vesicular exocytosis through a direct interaction with the SNARE protein complex comprising syntaxin, SNAP-25, and VAMP/synaptobrevin (Catterall 1999;Mochida et al 2003a,b;Weiss and Zamponi 2012). The site of this interaction is the "synprint" (synaptic protein interaction) region located in the large intracellular linker between domains II and III of Ca V (Sheng et al 1994Rettig et al 1996) in the case of Ca V 2.1 and Ca V 2.2 channels; disruption of this motif reduces the efficacy of neurotransmission (Catterall 1999), although emerging evidence suggests that other mechanisms or regulatory proteins, such as CASK, Mint-1, and Rab3-interacting molecules (RIMs), may also facilitate the presynaptic organization of calcium channels (Kaneko et al 2002;Maximov and Bezprozvanny 2002;Kiyonaka et al 2007;Liu et al 2011;Graf et al 2012). In addition to facilitating neurotransmission, the SNARE proteins also exert inhibitory modulation on Ca V 2.1; syntaxin reduces Ca V channel expression and inhibits its activity on heterologous expression (Bezprozvanny et al 1995).…”

Section: P/q- N- and R-type Channels In Synaptic Transmissionmentioning

confidence: 99%

The Role of Calcium Channels in Epilepsy

Rajakulendran

Hanna

2016

Cold Spring Harb Perspect Med

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A central theme in the quest to unravel the genetic basis of epilepsy has been the effort to elucidate the roles played by inherited defects in ion channels. The ubiquitous expression of voltage-gated calcium channels (VGCCs) throughout the central nervous system (CNS), along with their involvement in fundamental processes, such as neuronal excitability and synaptic transmission, has made them attractive candidates. Recent insights provided by the identification of mutations in the P/Q-type calcium channel in humans and rodents with epilepsy and the finding of thalamic T-type calcium channel dysfunction in the absence of seizures have raised expectations of a causal role of calcium channels in the polygenic inheritance of idiopathic epilepsy. In this review, we consider how genetic variation in neuronal VGCCs may influence the development of epilepsy.

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RIM-Binding Protein, a Central Part of the Active Zone, Is Essential for Neurotransmitter Release

Abstract: Transmitter release at the fly neuromuscular junction is abolished in the absence of a scaffold protein.

Cited by 285 publications

References 39 publications

Choroid plexus transcytosis and exosome shuttling deliver folate into brain parenchyma

Choroid plexus transcytosis and exosome shuttling deliver folate into brain parenchyma

Transmission, Development, and Plasticity of Synapses

The Role of Calcium Channels in Epilepsy

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