The role of Munc18‐1 in docking and exocytosis of peptide hormone vesicles in the anterior pituitary

Korteweg, Niki; Maia, Ascanio S.; Thompson, Brenda; Roubos, Eric W.; Burbach, J. Peter H.; Verhage, Matthijs

doi:10.1042/bc20040101

Cited by 25 publications

(27 citation statements)

References 42 publications

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“…This underlines the importance of munc-18 for the secretion of hormones from anterior pituitary cells. They suggested that munc-18 is important for the docking of vesicles, because large dense-core vesicles assembled close to, but not directly at the terminal membrane (Korteweg et al 2005). This is in contrast to the findings of Verhage et al (2000) that synaptic vesicles are distributed normally in synapses of munc-18 null mutant mice.…”

Section: Discussioncontrasting

confidence: 56%

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Estradiol differentially modulates the exocytotic proteins SNAP-25 and munc-18 in pituitary gonadotrophs

Weiß

Hüller²,

Polack³

et al. 2007

Journal of Molecular Endocrinology

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Long-term treatment with estradiol increases LH secretion from female gonadotrophs. The mechanisms are not fully clarified yet. Our previous data indicated that sexual steroids might affect late steps in GnRH signal transduction such as exocytosis. The secretion of hormones from neuroendocrine cells requires the merger of secretory vesicles with the plasma membrane. This regulated exocytosis is mediated by specific proteins, which are present in the pituitary gland. Here, we examined whether two of these crucial exocytotic proteins, SNAP-25 and munc-18, are affected by estradiol in female gonadotrophs. Female rat anterior pituitary cells and aT3-1 cells, derived from a murine immortalized gonadotroph cell line, were treated with 100 pM estradiol for 48 h. LH secretion of anterior pituitary cells, additionally stimulated with eight consecutive pulses of 1 nM GnRH for 15 min at an interval of 1 h, was determined by RIA. Gene expression was measured by quantitative RT-PCR and protein expression by immunoblotting. Additionally, quantitative RT-PCR was performed in single rat gonadotrophs to ascribe effects exclusively to intact gonadotrophs. Pulsatile GnRH enhanced the mRNA expression of SNAP-25 and munc-18 in accordance with the LH secretory response with the greatest increase at the third pulse of GnRH. Estradiol treatment further increased GnRH-induced LH secretion at all GnRH pulses. SNAP-25 gene expression was significantly decreased at the fifth GnRH pulse and unaffected at basal after 48 h of estradiol treatment. In contrast, munc-18 mRNA levels were not significantly affected by estradiol at different GnRH-pulses in mixed anterior pituitary cells, whereas munc-18 gene expression was significantly increased at basal. In aT3-1 cells and single gonadotrophs, long-term estradiol treatment significantly reduced SNAP-25 protein and gene expression. In contrast, the protein and gene expression of munc-18 was significantly enhanced in both aT3-1 cells and single gonadotrophs. In conclusion, munc-18 and SNAP-25 were oppositionally influenced by estradiol. The results suggest that estradiol modulates the expression of exocytotic proteins in gonadotrophs and thus affects LH secretion.

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Section: Discussioncontrasting

confidence: 56%

“…There are no reports that clarify the fate of SNAP-25 after exocytosis in the pituitary gland occurred. Korteweg et al (2005) tested hormone levels in the anterior pituitaries of munc-18 null mutant mice. They found very low levels of circulating hormones and enhanced intracellular hormones.…”

Section: Discussionmentioning

confidence: 99%

Estradiol differentially modulates the exocytotic proteins SNAP-25 and munc-18 in pituitary gonadotrophs

Weiß

Hüller²,

Polack³

et al. 2007

Journal of Molecular Endocrinology

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“…In light of our findings it is of interest to compare with studies made in another cell type, namely the pituitary somatotrophs, where co-existence of Munc18-1 and Munc18-2 has also been observed (52). Anterior pituitary cells from Munc18-1 null mutants did not exhibit a complete absence of stimulated peptide secretion from large dense core vesicles.…”

Section: Discussionmentioning

confidence: 85%

“…Munc18-2 has mostly been studied in epithelial tissues, where it controls apical regulated exocytosis, and in pancreatic acini, where it has been demonstrated to control Slp4a/ granuphilin-syntaxin interactions and amylase secretion (17,50). Coexpression of Munc18-1 and Munc18-2 has been confirmed in ␤-cells, somatotrophs in the anterior pituitary, mast cells, and PC12 cells (18,(52)(53)(54).…”

Section: Discussionmentioning

confidence: 99%

Munc18-1 and Munc18-2 Proteins Modulate β-Cell Ca2+ Sensitivity and Kinetics of Insulin Exocytosis Differently

Mandic

Skelin

Johansson

et al. 2011

Journal of Biological Chemistry

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Fast neurotransmission and slower hormone release share the same core fusion machinery consisting of SNARE (soluble N-ethylmaleimide-sensitive factor attachment protein receptor) proteins. In evoked neurotransmission, interactions between SNAREs and the Munc18-1 protein, a member of the Sec1/Munc18 (SM) protein family, are essential for exocytosis, whereas other SM proteins are dispensable. To address if the exclusivity of Munc18-1 demonstrated in neuroexocytosis also applied to fast insulin secretion, we characterized the presence and function of Munc18-1 and its closest homologue Munc18-2 in ␤-cell stimulus-secretion coupling. We show that pancreatic ␤-cells express both Munc18-1 and Munc18-2. The two Munc18 homologues exhibit different subcellular localization, and only Munc18-1 redistributes in response to glucose stimulation. However, both Munc18-1 and Munc18-2 augment glucose-stimulated hormone release. To maintain glucose homeostasis in the body, the pancreatic ␤-cell must in a controlled way produce, store, and secrete insulin in response to appropriate stimuli (1). Regulated membrane fusion resulting in insulin exocytosis in ␤-cells is managed by the same core SNARE 3 (soluble N-ethylmaleimide-sensitive factor (NSF) attachment protein receptor) fusion machinery that mediates release of chemical signals at highly specialized central neuronal synapses (2-4). Three conserved SNARE proteins, VAMP2, syntaxin 1A, and SNAP-25, connect vesicles with the plasma membrane by forming an exceptionally stable protein complex that holds the intrinsic, but slow, capability to perform lipid bilayer fusion (5). Except for the SNARE proteins, additional cooperating proteins are critical to guarantee speed and accuracy of diverse membrane fusion events occurring in excitable cells. Such a key accessory regulator in synaptic transmission is Munc18-1, a member of the Munc18 (mammalian homologue of the unc-18 gene) family (6). In addition to Munc18-1 (with two alternatively spliced variants, Munc18-1a and Munc18-1b), Munc18-2 and Munc18-3 isoforms have also been identified (7-9). Munc18-2, also named Munc18b or muSec1 (mammalian ubiquitously Sec1), is the closest homologue of Munc18-1, showing 63% amino acid sequence identity (7).The 67-kDa hydrophilic Munc18-1 protein has been shown to be necessary not only for vesicle exocytosis but also for docking of vesicles to the plasma membrane (10). Indeed, in the absence of Munc18-1 in neuronal cells, neither evoked nor spontaneous neurotransmission can operate (6). However, besides the reported positive effect of Munc18-1 in regulated exocytosis (6, 11-13), Munc18-1 has also been identified as a negative regulator of insulin secretion (14, 15). Still, Munc18-1 is primarily considered to be a neuronal protein, whereas the homologue Munc18-2 has a wider tissue expression profile. For instance, Munc18-2 is prominent in epithelial cells (16) and has been identified as a binding partner of Cab45, a Ca 2ϩ -binding protein prominent in pancreatic acini (17). Recently Cab45/ Munc18-2 was a...

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“…Although Munc18-1-deficient mice are known to have normal synaptic structures (i.e., docking of synaptic vesicles to the presynaptic plasma membrane is normal; Verhage et al, 2000), a defect in the dense-core vesicle docking to the plasma membrane in neuroendocrine cells has recently been reported (Voets et al, 2001;Korteweg et al, 2005). Moreover, Munc18-1 has been proposed to regulate more than one stage (e.g., docking and fusion) of dense-core vesicle exocytosis (Fisher et al, 2001;Graham et al, 2004;Ciufo et al, 2005), possibly by binding different binding partners (e.g., syntaxin-1a and Doc2; Verhage et al, 1997).…”

Section: Discussionmentioning

confidence: 99%

The Slp4-a Linker Domain Controls Exocytosis through Interaction with Munc18-1·Syntaxin-1a Complex

Tsuboi

Fukuda

2006

MBoC

107

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Synaptotagmin-like protein 4-a (Slp4-a)/granuphilin-a is specifically localized on dense-core vesicles in certain neuroendocrine cells and negatively controls dense-core vesicle exocytosis through specific interaction with Rab27A. However, the precise molecular mechanism of its inhibitory effect on exocytosis has never been elucidated and is still a matter of controversy. Here we show by deletion and chimeric analyses that the linker domain of Slp4-a interacts with the Munc18-1⅐syntaxin-1a complex by directly binding to Munc18-1 and that this interaction promotes docking of dense-core vesicles to the plasma membrane in PC12 cells. Despite increasing the number of plasma membrane docked vesicles, expression of Slp4-a strongly inhibited high-KCl-induced dense-core vesicle exocytosis. The inhibitory effect by Slp4-a is absolutely dependent on the linker domain of Slp4-a, because substitution of the linker domain of Slp4-a by that of Slp5 (the closest isoform of Slp4-a that cannot bind the Munc18-1⅐syntaxin-1a complex) completely abrogated the inhibitory effect. Our findings reveal a novel docking machinery for dense-core vesicle exocytosis: Slp4-a simultaneously interacts with Rab27A and Munc18-1 on the dense-core vesicle and with syntaxin-1a in the plasma membrane.

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The role of Munc18‐1 in docking and exocytosis of peptide hormone vesicles in the anterior pituitary

Cited by 25 publications

References 42 publications

Estradiol differentially modulates the exocytotic proteins SNAP-25 and munc-18 in pituitary gonadotrophs

Estradiol differentially modulates the exocytotic proteins SNAP-25 and munc-18 in pituitary gonadotrophs

Munc18-1 and Munc18-2 Proteins Modulate β-Cell Ca2+ Sensitivity and Kinetics of Insulin Exocytosis Differently

The Slp4-a Linker Domain Controls Exocytosis through Interaction with Munc18-1·Syntaxin-1a Complex

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