DOC2b is a SNARE regulator of glucose-stimulated delayed insulin secretion

Miyazaki, Mutsuko; Emoto, Masahiro; Fukuda, Naofumi; Hatanaka, Masayuki; Taguchi, Akihiko; Miyamoto, Sachiko; Tanizawa, Yukio

doi:10.1016/j.bbrc.2009.04.133

Cited by 20 publications

(30 citation statements)

References 33 publications

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“…Upon depolarization of neurons and neuroendocrine cells, increases in intracellular Ca 2+ ([Ca 2+ ] i ) drive the rapid translocation of Doc2β to the plasma membrane (20,21). In addition, stimulation of adipocytes with insulin and pancreatic B cells with glucose also trigger translocation of Doc2β to the plasma membrane (22,23). These findings are consistent with the idea that Doc2β functions as a Ca 2+ sensor for secretion, because it must be present at release sites to regulate exocytosis.…”

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confidence: 78%

Structural elements that underlie Doc2β function during asynchronous synaptic transmission

Xue

Gaffaney

Chapman

2015

Proc. Natl. Acad. Sci. U.S.A.

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Double C2-like domain-containing proteins alpha and beta (Doc2α and Doc2β) are tandem C2-domain proteins proposed to function as Ca 2+ sensors for asynchronous neurotransmitter release. Here, we systematically analyze each of the negatively charged residues that mediate binding of Ca 2+ to the β isoform. The Ca 2+ ligands in the C2A domain were dispensable for Ca 2+ -dependent translocation to the plasma membrane, with one exception: neutralization of D220 resulted in constitutive translocation. In contrast, three of the five Ca 2+ ligands in the C2B domain are required for translocation. Importantly, translocation was correlated with the ability of the mutants to enhance asynchronous release when overexpressed in neurons. Finally, replacement of specific Ca 2+ /lipid-binding loops of synaptotagmin 1, a Ca 2+ sensor for synchronous release, with corresponding loops from Doc2β, resulted in chimeras that yielded slower kinetics in vitro and slower excitatory postsynaptic current decays in neurons. Together, these data reveal the key determinants of Doc2β that underlie its function during the slow phase of synaptic transmission.-triggered synaptic vesicle (SV) exocytosis in nerve terminals is often a biphasic process consisting of a fast, synchronous phase, occurring within milliseconds of Ca 2+ influx, and a slow, asynchronous phase, which can persist for hundreds of milliseconds. Synaptotagmin 1 (syt1) is thought to function as a Ca 2+ sensor for the rapid phase of release (1-4). Although syt1-KO neurons display a complete loss of synchronous transmission, the asynchronous component persists (5-7), suggesting that distinct Ca 2+ sensors regulate these processes. Recently, a specific subset of membrane-trafficking proteins has been proposed to mediate asynchronous release selectively (8, 9), including another member of the syt family of Ca 2+ sensors, syt7 (10). Syt7 is unique in that it has the slowest intrinsic kinetics of all syt isoforms (11), so it is well suited to drive the slow phase of transmission. However, in mouse neurons, loss of syt7 has no effect on the decay kinetics of single evoked synaptic currents (10,(12)(13)(14); rather, syt7-KO neurons exhibited a reduction in synaptic vesicle replenishment (13). The double C2-domain (Doc2) proteins, which also exhibit slow kinetics in vitro, are Ca 2+ -binding proteins required for normal levels of asynchronous release in hippocampal neurons (15,16 To date, three isoforms of Doc2 have been identified: α, β, and γ. Doc2α is expressed only in brain (17), while Doc2β and γ are expressed in a variety of tissues, including the brain (18, 19); γ does not appear to sense Ca 2+ (19). During asynchronous transmission, Doc2 α and β are able to substitute for one another functionally (15), and because Doc2β can be generated more readily in bacteria, the current study is focused on this isoform. Under resting conditions, Doc2β is a cytosolic protein. Upon depolarization of neurons and neuroendocrine cells, increases in intracellular Ca 2+ ([Ca 2+ ] i ) drive t...

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supporting

confidence: 78%

Structural elements that underlie Doc2β function during asynchronous synaptic transmission

Xue

Gaffaney

Chapman

2015

Proc. Natl. Acad. Sci. U.S.A.

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“…Yet in a recent work performed in 3T3-L1 adipocytes, DOC2B showed cytosolic distribution and translocated to the cell membrane only following insulin addition. In addition, the translocation occurred at a slower rate (∼5 min [41,43]) compared to that measured in PC12 cells (∼2 s [13]) and chromaffin cells (unpublished data).…”

Section: Introductionmentioning

confidence: 55%

“…Support for these suggestions comes from the finding that during repeated stimulation, DOC2B enhances secretion gradually, and its effect becomes larger during later stimulations, suggesting that more than one stimulus is needed to reach its maximal effect [7]. In insulin-secreting cells, DOC2B is suspected of being a regulator of the second phase of insulin secretion (up to 60 s following stimulation) by interacting with syntaxin4 in a Ca 2+ -dependent manner [41,43]. The second phase of insulin secretion is slow and prolonged, and this correlates well with DOC2B's relatively slower rate of action at the PM and its ability to support enhanced secretion during repeated stimulations [7].…”

Section: Doc2b's Interacting Partnersmentioning

confidence: 86%

“…In recent years, several reports have been published on the physiological role of DOC2B, suggesting it to be a positive regulator of exocytosis. DOC2B associates with many proteins of the exocytotic machinery that are involved in different steps of the secretory cycle [7,[41][42][43]. Here, we suggest a possible model for DOC2B's involvement in calcium-triggered exocytosis.…”

Section: Doc2b's Interacting Partnersmentioning

confidence: 87%

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DOC2B, C2 Domains, and Calcium: A Tale of Intricate Interactions

2010

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Ca(+2)-dependent exocytosis involves vesicle docking, priming, fusion, and recycling. This process is performed and regulated by a vast number of synaptic proteins and depends on proper protein-protein and protein-lipid interactions. Double C2 domain (DOC2) is a protein family of three isoforms found while screening DNA libraries with a C2 probe. DOC2 has three domains: the Munc13-interacting domain and tandem C2s (designated C2A and C2B) connected by a short polar linker. The C2 domain binds phospholipids in a Ca(2+)-dependent manner. This review focuses on the ubiquitously expressed isoform DOC2B. Sequence alignment of the tandem C2 protein family in mouse revealed high homology (81%) between rabphilin-3A and DOC2B proteins. We created a structural model of DOC2B's C2A based on the crystal structure of rabphilin-3A with and without calcium and found that the calcium-binding loops of DOC2B move upon calcium binding, enabling efficient plasma membrane penetration of its C2A. Here, we discuss the potential relation between the DOC2B bioinformatical model and its function and suggest a possible working model for its interaction with other proteins of the exocytotic machinery, including Munc13, Munc18, and syntaxin.

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“…The involvement of rabphilin in calcium sensing has not been established, while Doc2b may function as a calcium sensor in spontaneous neurotransmitter release [ 65 ] . Doc2b may also have a role in chromaffi n cells [ 144 ] , pancreatic b -cells [ 145,146 ] and adipocytes [ 145,147 ] , although these remain to be confi rmed by genetic studies. E-Syts (extended synaptotagmin-like proteins) contain an N-terminal transmembrane region, but more than two C 2 domains [ 148,149 ] .…”

Section: Other Calcium-binding Proteinsmentioning

confidence: 94%

Calcium Sensing in Exocytosis

Gustavsson

Han

2012

Advances in Experimental Medicine and Biology

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Neurotransmitters, neuropeptides and hormones are released through regulated exocytosis of synaptic vesicles and large dense core vesicles. This complex and highly regulated process is orchestrated by SNAREs and their associated proteins. The triggering signal for regulated exocytosis is usually an increase in intracellular calcium levels. Besides the triggering role, calcium signaling modulates the precise amount and kinetics of vesicle release. Thus, it is a central question to understand the molecular machineries responsible for calcium sensing in exocytosis. Here we provide an overview of our current understanding of calcium sensing in neurotransmitter release and hormone secretion.

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DOC2b is a SNARE regulator of glucose-stimulated delayed insulin secretion

Cited by 20 publications

References 33 publications

Structural elements that underlie Doc2β function during asynchronous synaptic transmission

Structural elements that underlie Doc2β function during asynchronous synaptic transmission

DOC2B, C2 Domains, and Calcium: A Tale of Intricate Interactions

Calcium Sensing in Exocytosis

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