A minimal domain responsible for Munc13 activity

Basu, Jayeeta; Shen, Nan; Dulubova, Irina; Lu, Jun; Guan, R.; Guryev, Oleg; Grishin, Nick V.; Rosenmund, Christian; Rizo, Josep

doi:10.1038/nsmb1001

Cited by 188 publications

(260 citation statements)

References 13 publications

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“…Translocation of soluble Munc13-1 to the plasma membrane is thought to create additional priming sites, particularly when the membrane-bound Munc13-1 in the presynaptic active zone is functionally saturated (19). The Munc13-1 H567K/ϩ mice islet ␤-cells secreted more insulin than Munc13-1 ϩ/Ϫ mice, which we attribute to the fact that the Munc13-1 H567K mutant variant, although defective in its C1 domain, still has some capability of transducing its priming action since the priming domain was recently localized to a ␣-helical domain in the COOH-terminus (28,29,41). Consistently, overexpression of Munc13-1…”

Section: Munc13-1 Deficiency Reduces Insulin Secretionmentioning

confidence: 88%

“…5B). The reason for the better GSIS response of the Munc13-1 H567K/ϩ islets compared with the Munc13-1 ϩ/Ϫ islets is that the Munc13-1 H567K DAG-binding site mutant protein, although defective in its ability to translocate to the plasma membrane, contains an intact priming domain that is distinct from the DAG-binding site (28,29) and therefore is able to retain some priming function (19,22). Nonetheless, these results show that an intact C1 PMA/ DAG-binding domain of Munc13-1 is required for a fully efficacious potentiation of GSIS by PMA.…”

Section: Munc13-1mentioning

confidence: 99%

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Munc13-1 Deficiency Reduces Insulin Secretion and Causes Abnormal Glucose Tolerance

et al. 2006

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Munc13-1 is a diacylglycerol (DAG) receptor that is essential for synaptic vesicle priming. We recently showed that Munc13-1 is expressed in rodent and human islet ␤-cells and that its levels are reduced in islets of type 2 diabetic humans and rat models, suggesting that Munc13-1 deficiency contributes to the abnormal insulin secretion in diabetes. To unequivocally demonstrate the role of Munc13-1 in insulin secretion, we studied heterozygous Munc13-1 knockout mice (؉/؊), which exhibited elevated glucose levels during intraperitoneal glucose tolerance tests with corresponding lower serum insulin levels. Munc13-1؉/؊ mice exhibited normal insulin tolerance, indicating that a primary islet ␤-cell secretory defect is the major cause of their hyperglycemia. Consistently, glucosestimulated insulin secretion was reduced 50% in isolated Munc13-1 ؉/؊ islets and was only partially rescued by phorbol ester potentiation. The corresponding alterations were minor in mice expressing one allele of a Munc13-1 mutant variant, which does not bind DAG (H567K/؉). Capacitance measurements of Munc13-1 ؉/؊ and Munc13-1 H567k/؉ islet ␤-cells revealed defects in granule priming, including the initial size and refilling of the releasable pools, which become accentuated by phorbol ester potentiation. We conclude that Munc13-1 plays an important role in glucosestimulated insulin secretion and that Munc13-1 deficiency in the pancreatic islets as occurs in diabetes can reduce insulin secretion sufficient to cause abnormal glucose homeostasis. Diabetes 55: [1421][1422][1423][1424][1425][1426][1427][1428][1429] 2006 N ormal glucose-stimulated insulin secretion (GSIS) from pancreatic islets follows a biphasic pattern (1). The first phase is a robust release lasting ϳ5-10 min and is triggered by ATPsensitive K ϩ channel-dependent Ca 2ϩ entry into the pancreatic ␤-cells. This is followed by a second phase and sustained release, which is regulated by second messengers including diacyglycerol (DAG), cAMP, and permissive elevated levels of Ca 2ϩ (2). In patients with type 2 diabetes, this pattern of secretion is perturbed, resulting in an abolished first phase and a blunted second phase (2). It is generally accepted that the biphasic secretion pattern is contributed by the release of spatially and functionally distinct insulin granules. The morphologically docked granule pool at the plasma membrane contains Ͻ10% of the total of Ͼ10,000 insulin granules per cell, and only a fraction (20 -30%) of the docked pool is primed and fusion competent for immediate release (3). It is the release of this docked and primed granule pool that contributes to the first phase of insulin secretion (2-4). One of the aims of the present study was to identify the proteins that prime insulin granules for release.As in neurons (5), exocytosis in pancreatic islet ␤-cells is regulated by the SNARE (soluble N-ethylmaleimidesensitive factor attachment protein [SNAP] receptor) proteins VAMP, SNAP-25, and syntaxin-1A (6). These SNARE proteins form a ternary complex capable of ...

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Section: Munc13-1 Deficiency Reduces Insulin Secretionmentioning

confidence: 88%

Section: Munc13-1mentioning

confidence: 99%

Munc13-1 Deficiency Reduces Insulin Secretion and Causes Abnormal Glucose Tolerance

et al. 2006

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“…It is tempting to suspect that some of the interactions described here might be influenced by them. The C-terminal half of Munc13-1, in particular, is responsible for the synaptic vesicle priming activity of the protein, which in turn is thought to be regulated by signal input through the N-terminal half (Basu et al, 2005;Stevens et al, 2005). Our findings add three new molecular interactions of the Munc13-1 N-terminal half (with CAST1, Aczonin-CC3, and Bassoon-CT) to those already known (with itself, Rim-ZF, Ca 2ϩ /calmodulin, and diacylglycerol), significantly expanding the scope of its regulatory potential.…”

Section: Discussionmentioning

confidence: 99%

A Protein Interaction Node at the Neurotransmitter Release Site: Domains of Aczonin/Piccolo, Bassoon, CAST, and Rim Converge on the N-Terminal Domain of Munc13-1

Wang

Hu²,

Zięba³

et al. 2009

J. Neurosci.

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Multidomain scaffolding proteins organize the molecular machinery of neurotransmitter vesicle dynamics during synaptogenesis and synaptic activity. We find that domains of five active zone proteins converge on an interaction node that centers on the N-terminal region of Munc13-1 and includes the zinc-finger domain of Rim1, the C-terminal region of Bassoon, a segment of CAST1/ELKS2, and the third coiled-coil domain (CC3) of either Aczonin/Piccolo or Bassoon. This multidomain complex may constitute a center for the physical and functional integration of the protein machinery at the active zone. An additional connection between Aczonin and Bassoon is mediated by the second coiled-coil domain of Aczonin. Recombinant Aczonin-CC3, expressed in cultured neurons as a green fluorescent protein fusion protein, is targeted to synapses and suppresses vesicle turnover, suggesting involvements in synaptic assembly as well as activity. Our findings show that Aczonin, Bassoon, CAST1, Munc13, and Rim are closely and multiply interconnected, they indicate that Aczonin-CC3 can actively participate in neurotransmitter vesicle dynamics, and they highlight the N-terminal region of Munc13-1 as a hub of protein interactions by adding three new binding partners to its mechanistic potential in the control of synaptic vesicle priming.

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“…The corresponding gene products share a common domain structure in their C-terminal halves, which is functionally essential for priming activity (Basu et al, 2005;Stevens et al, 2005) and exhibits structural homology to vesicle tethering factors (Li et al, 2011). Two more distantly related genes encode the Munc13-like proteins Munc13-4 and Bap3/Baiap3 (Koch et al, 2000), which play key roles in non-neuronal cells (e.g., in the immune system) (Feldmann et al, 2003;Pivot-Pajot et al, 2008).…”

Section: Introductionmentioning

confidence: 99%

Munc13-Independent Vesicle Priming at Mouse Photoreceptor Ribbon Synapses

Cooper

Hemmerlein²,

Ammermüller³

et al. 2012

Journal of Neuroscience

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Munc13 proteins are essential regulators of exocytosis. In hippocampal glutamatergic neurons, the genetic deletion of Munc13s results in the complete loss of primed synaptic vesicles (SVs) in direct contact with the presynaptic active zone membrane, and in a total block of neurotransmitter release. Similarly drastic consequences of Munc13 loss are detectable in hippocampal and striatal GABAergic neurons. We show here that, in the adult mouse retina, the two Munc13-2 splice variants bMunc13-2 and ubMunc13-2 are selectively localized to conventional and ribbon synapses, respectively, and that ubMunc13-2 is the only Munc13 isoform in mature photoreceptor ribbon synapses. Strikingly, the genetic deletion of ubMunc13-2 has little effect on synaptic signaling by photoreceptor ribbon synapses and does not prevent membrane attachment of synaptic vesicles at the photoreceptor ribbon synaptic site. Thus, photoreceptor ribbon synapses and conventional synapses differ fundamentally with regard to their dependence on SV priming proteins of the Munc13 family. Their function is only moderately affected by Munc13 loss, which leads to slight perturbations of signal integration in the retina.

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A minimal domain responsible for Munc13 activity

Cited by 188 publications

References 13 publications

Munc13-1 Deficiency Reduces Insulin Secretion and Causes Abnormal Glucose Tolerance

Munc13-1 Deficiency Reduces Insulin Secretion and Causes Abnormal Glucose Tolerance

A Protein Interaction Node at the Neurotransmitter Release Site: Domains of Aczonin/Piccolo, Bassoon, CAST, and Rim Converge on the N-Terminal Domain of Munc13-1

Munc13-Independent Vesicle Priming at Mouse Photoreceptor Ribbon Synapses

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