Basic mechanisms for recognition and transport of synaptic cargos

Department of Neuroscience, Erasmus Medical Center, 3015GE, Rotterdam, The Netherlands.
Molecular Brain (Impact Factor: 4.9). 09/2009; 2(1):25. DOI: 10.1186/1756-6606-2-25
Source: PubMed


Synaptic cargo trafficking is essential for synapse formation, function and plasticity. In order to transport synaptic cargo, such as synaptic vesicle precursors, mitochondria, neurotransmitter receptors and signaling proteins to their site of action, neurons make use of molecular motor proteins. These motors operate on the microtubule and actin cytoskeleton and are highly regulated so that different cargos can be transported to distinct synaptic specializations at both pre- and post-synaptic sites. How synaptic cargos achieve specificity, directionality and timing of transport is a developing area of investigation. Recent studies demonstrate that the docking of motors to their cargos is a key control point. Moreover, precise spatial and temporal regulation of motor-cargo interactions is important for transport specificity and cargo recruitment. Local signaling pathways Ca2+ influx, CaMKII signaling and Rab GTPase activity regulate motor activity and cargo release at synaptic locations. We discuss here how different motors recognize their synaptic cargo and how motor-cargo interactions are regulated by neuronal activity.

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Available from: Max Schlager, Oct 05, 2015
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    • "Dysregulation of DCV transport and fusion is associated with cognitive and post-traumatic stress disorders (Sadakata et al., 2007b; Meyer-Lindenberg et al., 2011; Sah and Geracioti, 2013). DCVs bud off at the Golgi network (Kim et al., 2006) and are transported via microtubule-based motor proteins (Hirokawa et al., 2009; Schlager and Hoogenraad, 2009). High-frequency firing facilitates DCV fusion and the resultant calcium influx triggers SNARE complex-dependent DCV secretion (Bartfai et al., 1988; Hartmann et al., 2001; de Wit et al., 2009; van de Bospoort et al., 2012). "
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    ABSTRACT: Neuropeptides released from dense-core vesicles (DCVs) modulate neuronal activity, but the molecules driving DCV secretion in mammalian neurons are largely unknown. We studied the role of calcium-activator protein for secretion (CAPS) proteins in neuronal DCV secretion at single vesicle resolution. Endogenous CAPS-1 co-localized with synaptic markers but was not enriched at every synapse. Deletion of CAPS-1 and CAPS-2 did not affect DCV biogenesis, loading, transport or docking, but DCV secretion was reduced by 70% in CAPS-1/CAPS-2 double null mutant (DKO) neurons and remaining fusion events required prolonged stimulation. CAPS deletion specifically reduced secretion of stationary DCVs. CAPS-1-EYFP expression in DKO neurons restored DCV secretion, but CAPS-1-EYFP and DCVs rarely traveled together. Synaptic localization of CAPS-1-EYFP in DKO neurons was calcium dependent and DCV fusion probability correlated with synaptic CAPS-1-EYFP expression. These data indicate that CAPS-1 promotes fusion competence of immobile (tethered) DCVs in presynaptic terminals and that CAPS-1 localization to DCVs is probably not essential for this role. DOI:
    eLife Sciences 02/2015; 4(4):e05438. DOI:10.7554/eLife.05438 · 9.32 Impact Factor
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    • "The transport of vesicular cargo depends on selective association with microtubule-based motors (Hirokawa et al., 2010; Schlager and Hoogenraad, 2009) whose activity and cargo association are regulated by diverse cellular signals (Guillaud et al., 2008; Hirokawa et al., 2010; Johansson et al., 2007; Macaskill et al., 2009; Niwa et al., 2008). Among microtubule motors, KIF17 regulates the trafficking of select dendritic cargo, and phosphorylation of KIF17 by CaMKII on serine 1029 abrogates binding to the NMDA receptor/CASK/Mint1 complex (Guillaud et al., 2008). "
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    ABSTRACT: Localized signaling in neuronal dendrites requires tight spatial control of membrane composition. Upon initial synthesis, nascent secretory cargo in dendrites exits the endoplasmic reticulum (ER) from local zones of ER complexity that are spatially coupled to post-ER compartments. Although newly synthesized membrane proteins can be processed locally, the mechanisms that control the spatial range of secretory cargo transport in dendritic segments are unknown. Here, we monitored the dynamics of nascent membrane proteins in dendritic post-ER compartments under regimes of low or increased neuronal activity. In response to activity blockade, post-ER carriers are highly mobile and are transported over long distances. Conversely, increasing synaptic activity dramatically restricts the spatial scale of post-ER trafficking along dendrites. This activity-induced confinement of secretory cargo requires site-specific phosphorylation of the kinesin motor KIF17 by Ca(2+)/calmodulin-dependent protein kinases (CaMK). Thus, the length scales of early secretory trafficking in dendrites are tuned by activity-dependent regulation of microtubule-dependent transport.
    Cell Reports 06/2014; 7(6). DOI:10.1016/j.celrep.2014.05.028 · 8.36 Impact Factor
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    • "KIF17 transports NMDA receptor vesicles (Setou et al., 2002) and KIF5 has been shown to be involved in the transport of GABA receptor vesicles (Twelvetrees et al., 2010), mRNAs bound to large protein complexes (Dictenberg et al., 2008; Kanai et al., 2004), AMPA receptor-containing vesicles (Setou et al., 2002), and EphB2 receptors (Hoogenraad et al., 2005). For some of these cargos, the molecular motors bind to adaptor molecules (Hirokawa et al., 2010; Schlager and Hoogenraad, 2009). GRIP1 is a multi-PDZ-containing protein that binds to KIF5 to transport AMPA receptors and EphB2 receptors to dendrites (Hoogenraad et al., 2005; Setou et al., 2002). "
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    ABSTRACT: Regulation of cargo transport via adaptor molecules is essential for neuronal development. However, the role of PDZ scaffolding proteins as adaptors in neuronal cargo trafficking is still poorly understood. Here, we show by genetic deletion in mice that the multi-PDZ domain scaffolding protein glutamate receptor interacting protein 1 (GRIP1) is required for dendrite development. We identify an interaction between GRIP1 and 14-3-3 proteins that is essential for the function of GRIP1 as an adaptor protein in dendritic cargo transport. Mechanistically, 14-3-3 binds to the kinesin-1 binding region in GRIP1 in a phospho-dependent manner and detaches GRIP1 from the kinesin-1 motor protein complex thereby regulating cargo transport. A single point mutation in the Thr956 of GRIP1 in transgenic mice impairs dendritic development. Together, our results show a regulatory role for GRIP1 during microtubule-based transport and suggest a crucial function for 14-3-3 proteins in controlling kinesin-1 motor attachment during neuronal development.
    Developmental Cell 02/2014; 28(4):381-93. DOI:10.1016/j.devcel.2014.01.018 · 9.71 Impact Factor
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