Munc18-1 redistributes in nerve terminals in an activity- and PKC-dependent manner

Cijsouw, Tony; Weber, Jens P.; Broeke, Jurjen H.; Broek, Jantine A.C.; Schut, Desiree; Kroon, Tim; Saarloos, Ingrid; Verhage, Matthijs; Toonen, Ruud F.

doi:10.1083/jcb.201308026

Cited by 47 publications

(60 citation statements)

References 87 publications

(113 reference statements)

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“…Mammalian MUNC18 and homologous C. elegans UNC-18 interact with SNARE protein complexes to regulate docking, priming, and exocytosis of SVs and DCVs (50,51,57,58,(61)(62)(63). Repetitive electrical stimulation of murine auditory and cerebellar synapses substantially raises the rate of NT release (15,54).…”

Section: Discussionmentioning

confidence: 99%

“…Increased exocytosis persists for a long interval after stimulation is terminated. This important form of presynaptic plasticity is controlled by cPKC-mediated, multisite phosphorylation of MUNC18 (54,(56)(57)(58). C. elegans reduces its rate of locomotory muscle contractions by ϳ65% immediately after transfer to a noxious, supraphysiological temperature (28°C).…”

Section: Discussionmentioning

confidence: 99%

“…In separate constructs, relevant serines were mutated to Ala. WT and mutated versions of 32-kDa GST-UNC-18 288-339 fusion proteins were expressed in Escherichia coli and purified by affinity chromatography (Fig. 7B) Replacement of PKC substrate sites in Munc18 with Ala creates DN proteins that inhibit Ca 2ϩ -and DAG-dependent enhancement of SV or DCV exocytosis in stimulated neurons (54,(56)(57)(58). Therefore, mutations described above were introduced into cDNA encoding full-length UNC-18.…”

Section: Pkc-2 Links Thermosensory Signals To Learned Behaviormentioning

confidence: 99%

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A Calcium- and Diacylglycerol-Stimulated Protein Kinase C (PKC), Caenorhabditis elegans PKC-2, Links Thermal Signals to Learned Behavior by Acting in Sensory Neurons and Intestinal Cells

Land

Rubin

2017

Molecular and Cellular Biology

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Ca 2ϩ -and diacylglycerol (DAG)-activated protein kinase C (cPKC) promotes learning and behavioral plasticity. However, knowledge of in vivo regulation and exact functions of cPKCs that affect behavior is limited. We show that PKC-2, a Caenorhabditis elegans cPKC, is essential for a complex behavior, thermotaxis. C. elegans memorizes a nutrient-associated cultivation temperature (T c ) and migrates along the T c within a 17 to 25°C gradient. pkc-2 gene disruption abrogated thermotaxis; a PKC-2 transgene, driven by endogenous pkc-2 promoters, restored thermotaxis behavior in pkc-2 Ϫ/Ϫ animals. Cell-specific manipulation of PKC-2 activity revealed that thermotaxis is controlled by cooperative PKC-2-mediated signaling in both AFD sensory neurons and intestinal cells. Cold-directed migration (cryophilic drive) precedes T c tracking during thermotaxis. Analysis of temperature-directed behaviors elicited by persistent PKC-2 activation or inhibition in AFD (or intestine) disclosed that PKC-2 regulates initiation and duration of cryophilic drive. In AFD neurons, PKC-2 is a Ca 2ϩ sensor and signal amplifier that operates downstream from cyclic GMP-gated cation channels and distal guanylate cyclases. UNC-18, which regulates neurotransmitter and neuropeptide release from synaptic vesicles, is a critical PKC-2 effector in AFD. UNC-18 variants, created by mutating Ser 311 or Ser 322 , disrupt thermotaxis and suppress PKC-2-dependent cryophilic migration.KEYWORDS C. elegans signal integration, MUNC18 and UNC-18, calcium, diacylglycerol-activated PKC, cyclic GMP-gated channel, protein kinase C, regulation of learned behavior, sensory neuron, signal transduction, thermotaxis D iacylglycerol (DAG) and free cytoplasmic Ca 2ϩ mediate actions of hormones, neurotransmitters (NTs), and other stimuli that activate phospholipases C␤ and C␥ (1). Conventional protein kinase C isoforms (cPKCs ␣, ␤I, ␤II, and ␥) are widely expressed effectors of Ca 2ϩ and DAG in mammalian tissues (2-5). cPKCs are translocated to membranes and activated by binding Ca 2ϩ and DAG via their respective C2 and C1 domains. Thus, cPKCs are poised to receive, amplify, and disseminate the complete spectrum of intracellular signals generated by phospholipase C activation. Accordingly, cPKCs often couple extracellular stimuli to physiological processes that are coregulated by dynamic changes in Ca 2ϩ and DAG levels. In contrast, novel PKC isoforms (nPKCs ␦, , , and ) are activated by DAG alone.Some cell functions are redundantly regulated by combinations of PKCs. However, individual cPKCs can control key aspects of homeostasis or, when misregulated, promote pathological processes. For example, PKC␣ selectively regulates cardiac contrac-

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Pkc-2 Links Thermosensory Signals To Learned Behaviormentioning

confidence: 99%

See 1 more Smart Citation

A Calcium- and Diacylglycerol-Stimulated Protein Kinase C (PKC), Caenorhabditis elegans PKC-2, Links Thermal Signals to Learned Behavior by Acting in Sensory Neurons and Intestinal Cells

Land

Rubin

2017

Molecular and Cellular Biology

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“…Presynaptic proteins can be delivered from intracellular pools via synaptic vesicle protein transport vesicles (STVs), piccolo-bassoon transport vesicles (PTVs), or dense-core vesicles (DCVs; Ahmari et al, 2000;Zhai et al, 2001;Sabo et al, 2006;de Wit et al, 2009a;Bury and Sabo, 2011;van de Bospoort et al, 2012). In addition, synaptic membrane proteins can be distributed by lateral diffusion of surface populations (Ribrault et al, 2011;Chang et al, 2012;Cijsouw et al, 2014;Schneider et al, 2015). Because neurotransmission differs between synapses even of the same neuron (Rozov et al, 2001;Ermolyuk et al, 2012), regulated trafficking of synaptic components contributes to their functional specification (Lau and Zukin, 2007;Vithlani et al, 2011;Anggono and Huganir, 2012;Dolphin, 2012;Chia et al, 2013).…”

Section: Introductionmentioning

confidence: 99%

“…Nrxns represent a polymorphic family of differentially distributed, alternatively spliced molecules Schreiner et al, 2014;Treutlein et al, 2014), for which an increasing number of binding partners provide extracellular cues (Ichtchenko et al, 1995;Missler et al, 1998;Sugita et al, 2001;Boucard et al, 2005;Ko et al, 2009;de Wit et al, 2009b;Matsuda and Yuzaki, 2011;Boucard et al, 2012;Reissner et al, 2014). Both ␣-neurexin (␣Nrxn), with its large extracellular domain, and the shorter ␤-neurexin (␤Nrxn) are able to differentiate synapses in vitro (Dean et al, 2003;Graf et al, 2004;Nam and Chen, 2005).…”

Section: Introductionmentioning

confidence: 99%

Regulated Dynamic Trafficking of Neurexins Inside and Outside of Synaptic Terminals

et al. 2015

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Synapses depend on trafficking of key membrane proteins by lateral diffusion from surface populations and by exocytosis from intracellular pools. The cell adhesion molecule neurexin (Nrxn) plays essential roles in synapses, but the dynamics and regulation of its trafficking are unknown. Here, we performed single-particle tracking and live imaging of transfected, epitope-tagged Nrxn variants in cultured rat and mouse wild-type or knock-out neurons. We observed that structurally larger ␣Nrxn molecules are more mobile in the plasma membrane than smaller ␤Nrxns because ␣Nrxns displayed higher diffusion coefficients in extrasynaptic regions and excitatory or inhibitory terminals. We found that well characterized interactions with extracellular binding partners regulate the surface mobility of Nrxns. Binding to neurexophilin-1 (Nxph1) reduced the surface diffusion of ␣Nrxns when both molecules were coexpressed. Conversely, impeding other interactions by insertion of splice sequence #4 or removal of extracellular Ca 2ϩ augmented the mobility of ␣Nrxns and ␤Nrxns. We also determined that fast axonal transport delivers Nrxns to the neuronal surface because Nrxns comigrate as cargo on synaptic vesicle protein transport vesicles (STVs). Unlike surface mobility, intracellular transport of ␤Nrxn ϩ STVs was faster than that of ␣Nrxns, but both depended on the microtubule motor protein KIF1A and neuronal activity regulated the velocity. Large spontaneous fusion of Nrxn ϩ STVs occurred simultaneously with synaptophysin on axonal membranes mostly outside of active presynaptic terminals. Surface Nrxns enriched at synaptic terminals where ␣Nrxns and Nxph1/␣Nrxns recruited GABA A R subunits. Therefore, our results identify regulated dynamic trafficking as an important property of Nrxns that corroborates their function at synapses.

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SNARE Proteins in Synaptic Vesicle Fusion

Palfreyman,

West,

Jorgensen

2023

Advances in Neurobiology

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Munc18-1 redistributes in nerve terminals in an activity- and PKC-dependent manner

Abstract: PKC-dependent dynamic control of Munc18-1 levels enables individual synapses to tune their output during periods of activity.

Cited by 47 publications

References 87 publications

A Calcium- and Diacylglycerol-Stimulated Protein Kinase C (PKC), Caenorhabditis elegans PKC-2, Links Thermal Signals to Learned Behavior by Acting in Sensory Neurons and Intestinal Cells

A Calcium- and Diacylglycerol-Stimulated Protein Kinase C (PKC), Caenorhabditis elegans PKC-2, Links Thermal Signals to Learned Behavior by Acting in Sensory Neurons and Intestinal Cells

Regulated Dynamic Trafficking of Neurexins Inside and Outside of Synaptic Terminals

SNARE Proteins in Synaptic Vesicle Fusion

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