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Molecular mechanism of priming of ex...

Kwan, Edwin.

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Molecular mechanism of priming of exocytosis of insulin -containing granules.

Record Type:	Electronic resources : Monograph/item
Title/Author:	Molecular mechanism of priming of exocytosis of insulin -containing granules./
Author:	Kwan, Edwin.
Published:	Ann Arbor : ProQuest Dissertations & Theses, : 2007,
Description:	212 p.
Notes:	Source: Dissertations Abstracts International, Volume: 70-04, Section: B.
Contained By:	Dissertations Abstracts International70-04B.
Subject:	Cellular biology. -
Online resource:	http://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=NR39646
ISBN:	9780494396469

Molecular mechanism of priming of exocytosis of insulin -containing granules.
Kwan, Edwin.

Molecular mechanism of priming of exocytosis of insulin -containing granules. - Ann Arbor : ProQuest Dissertations & Theses, 2007 - 212 p.

Source: Dissertations Abstracts International, Volume: 70-04, Section: B.

Thesis (Ph.D.)--University of Toronto (Canada), 2007.

This item must not be sold to any third party vendors.

Exocytosis of insulin secretory granules (SGs) in the pancreatic β-cell involves a sequence of regulated exocytotic events, whose normal function and adaptation to increase in demand are essential for the maintenance of glucose homeostasis. These events comprise the trafficking and docking of SGs to the plasma membrane (PM), followed by fusion triggered by Ca 2+. Studies have unraveled post-docking steps mediated by novel factors, which by their interactions with SNARE- and SNARE-associated proteins, confer the docked SGs fusion competence. These priming steps define the releasable pool of SGs which accounts for the first insulin secretion phase, and controls the rate at which SGs are replenished for the second secretion phase. One aspect of this thesis is to examine the role of Munc13-1 protein in the regulation of priming of SGs. Studies employing transgenic mouse models suggest that Munc13-1 is important for the maintenance of glucose homeostasis. Electrophysiological studies show that Munc 13-1 regulates the priming and refilling of primed releasable SGs. The second aspect of the thesis is to investigate the mechanism, at the levels of fusion between the PM and SG membrane and that between SG, which underlie cAMP-induced potentiation of insulin secretion. Microscopy studies suggest that cAMP/Glucagon-like Peptide-1 (GLP-1) stimulation potentiates insulin secretion in part by promoting the number of docked SGs and sequential exocytotic events. It is further indicated that Exchange protein directly activated by cAMP (Epac)-catalyzed signaling pathway and Protein-kinase A (PKA)-catalyzed signaling pathway intersect in common and distinct steps in the potentiation; Epac activation primarily regulates the number of PM exocytotic events, whereas PKA activation stimulates fusion of oncoming SGs with SGs already undergoing exocytosis. The two pathways act synergistically to effect the full potentiating effect of cAMP stimulation. In Munc 13-1-deficient mouse models, Epac activation exerts a synergistic action in assisting PKA activation to rescue the exocytotic defects caused by Munc13-1 deficiency by promoting the priming actions of Munc13-1 via Rim2 to Munc 13-1 interaction.

ISBN: 9780494396469Subjects--Topical Terms:

3172791
Cellular biology.

Molecular mechanism of priming of exocytosis of insulin -containing granules.
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100 1 $a Kwan, Edwin. $3 3436557
245 1 0 $a Molecular mechanism of priming of exocytosis of insulin -containing granules.
260 1 $a Ann Arbor : $b ProQuest Dissertations & Theses, $c 2007
300 $a 212 p.
500 $a Source: Dissertations Abstracts International, Volume: 70-04, Section: B.
500 $a Publisher info.: Dissertation/Thesis.
502 $a Thesis (Ph.D.)--University of Toronto (Canada), 2007.
506 $a This item must not be sold to any third party vendors.
506 $a This item must not be added to any third party search indexes.
520 $a Exocytosis of insulin secretory granules (SGs) in the pancreatic β-cell involves a sequence of regulated exocytotic events, whose normal function and adaptation to increase in demand are essential for the maintenance of glucose homeostasis. These events comprise the trafficking and docking of SGs to the plasma membrane (PM), followed by fusion triggered by Ca 2+. Studies have unraveled post-docking steps mediated by novel factors, which by their interactions with SNARE- and SNARE-associated proteins, confer the docked SGs fusion competence. These priming steps define the releasable pool of SGs which accounts for the first insulin secretion phase, and controls the rate at which SGs are replenished for the second secretion phase. One aspect of this thesis is to examine the role of Munc13-1 protein in the regulation of priming of SGs. Studies employing transgenic mouse models suggest that Munc13-1 is important for the maintenance of glucose homeostasis. Electrophysiological studies show that Munc 13-1 regulates the priming and refilling of primed releasable SGs. The second aspect of the thesis is to investigate the mechanism, at the levels of fusion between the PM and SG membrane and that between SG, which underlie cAMP-induced potentiation of insulin secretion. Microscopy studies suggest that cAMP/Glucagon-like Peptide-1 (GLP-1) stimulation potentiates insulin secretion in part by promoting the number of docked SGs and sequential exocytotic events. It is further indicated that Exchange protein directly activated by cAMP (Epac)-catalyzed signaling pathway and Protein-kinase A (PKA)-catalyzed signaling pathway intersect in common and distinct steps in the potentiation; Epac activation primarily regulates the number of PM exocytotic events, whereas PKA activation stimulates fusion of oncoming SGs with SGs already undergoing exocytosis. The two pathways act synergistically to effect the full potentiating effect of cAMP stimulation. In Munc 13-1-deficient mouse models, Epac activation exerts a synergistic action in assisting PKA activation to rescue the exocytotic defects caused by Munc13-1 deficiency by promoting the priming actions of Munc13-1 via Rim2 to Munc 13-1 interaction.
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