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Dev Cell. 2018 May 7;45(3):347-361.e5. doi: 10.1016/j.devcel.2018.03.013. Epub 2018 Apr 12.

Synaptotagmin 4 Regulates Pancreatic β Cell Maturation by Modulating the Ca2+ Sensitivity of Insulin Secretion Vesicles.

Author information

1
Department of Cell and Developmental Biology, Vanderbilt University School of Medicine, Department of Veterans Affairs, Tennessee Valley Health Authority, Nashville, TN 37232, USA; Center for Stem Cell Biology, Vanderbilt University School of Medicine, Department of Veterans Affairs, Tennessee Valley Health Authority, Nashville, TN 37232, USA; The Program of Developmental Biology, Vanderbilt University School of Medicine, Department of Veterans Affairs, Tennessee Valley Health Authority, Nashville, TN 37232, USA.
2
Department of Molecular Physiology and Biophysics, Vanderbilt University School of Medicine, Department of Veterans Affairs, Tennessee Valley Health Authority, Nashville, TN 37232, USA.
3
China-Japan Friendship Hospital, Beijing 100029, P. R. China.
4
Department of Biomedical Informatics, Harvard Medical School, Boston, MA 02115, USA.
5
Department of Cell and Developmental Biology, Vanderbilt University School of Medicine, Department of Veterans Affairs, Tennessee Valley Health Authority, Nashville, TN 37232, USA.
6
Diabetes Center, UCSF, San Francisco, CA 94143, USA.
7
Laboratory of Metabolic Medicine, Singapore Bioimaging Consortium, Singapore, Singapore.
8
Department of Ophthalmology, Mary M. and Sash A. Spencer Center for Vision Research, Stanford University School of Medicine, Palo Alto, CA 94304, USA.
9
Department of Cell and Developmental Biology, Vanderbilt University School of Medicine, Department of Veterans Affairs, Tennessee Valley Health Authority, Nashville, TN 37232, USA; Center for Stem Cell Biology, Vanderbilt University School of Medicine, Department of Veterans Affairs, Tennessee Valley Health Authority, Nashville, TN 37232, USA; Department of Molecular Physiology and Biophysics, Vanderbilt University School of Medicine, Department of Veterans Affairs, Tennessee Valley Health Authority, Nashville, TN 37232, USA.
10
Institute for Biomedical Informatics and Department of Genetics, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA.
11
Department of Cell and Developmental Biology, Vanderbilt University School of Medicine, Department of Veterans Affairs, Tennessee Valley Health Authority, Nashville, TN 37232, USA; Center for Stem Cell Biology, Vanderbilt University School of Medicine, Department of Veterans Affairs, Tennessee Valley Health Authority, Nashville, TN 37232, USA; The Program of Developmental Biology, Vanderbilt University School of Medicine, Department of Veterans Affairs, Tennessee Valley Health Authority, Nashville, TN 37232, USA; Department of Molecular Physiology and Biophysics, Vanderbilt University School of Medicine, Department of Veterans Affairs, Tennessee Valley Health Authority, Nashville, TN 37232, USA; Department of Medicine, Vanderbilt University School of Medicine, Department of Veterans Affairs, Tennessee Valley Health Authority, Nashville, TN 37232, USA.
12
Department of Molecular Physiology and Biophysics, Vanderbilt University School of Medicine, Department of Veterans Affairs, Tennessee Valley Health Authority, Nashville, TN 37232, USA. Electronic address: david.a.jacobson@vanderbilt.edu.
13
Department of Cell and Developmental Biology, Vanderbilt University School of Medicine, Department of Veterans Affairs, Tennessee Valley Health Authority, Nashville, TN 37232, USA; Center for Stem Cell Biology, Vanderbilt University School of Medicine, Department of Veterans Affairs, Tennessee Valley Health Authority, Nashville, TN 37232, USA; The Program of Developmental Biology, Vanderbilt University School of Medicine, Department of Veterans Affairs, Tennessee Valley Health Authority, Nashville, TN 37232, USA. Electronic address: guoqiang.gu@vanderbilt.edu.

Abstract

Islet β cells from newborn mammals exhibit high basal insulin secretion and poor glucose-stimulated insulin secretion (GSIS). Here we show that β cells of newborns secrete more insulin than adults in response to similar intracellular Ca2+ concentrations, suggesting differences in the Ca2+ sensitivity of insulin secretion. Synaptotagmin 4 (Syt4), a non-Ca2+ binding paralog of the β cell Ca2+ sensor Syt7, increased by ∼8-fold during β cell maturation. Syt4 ablation increased basal insulin secretion and compromised GSIS. Precocious Syt4 expression repressed basal insulin secretion but also impaired islet morphogenesis and GSIS. Syt4 was localized on insulin granules and Syt4 levels inversely related to the number of readily releasable vesicles. Thus, transcriptional regulation of Syt4 affects insulin secretion; Syt4 expression is regulated in part by Myt transcription factors, which repress Syt4 transcription. Finally, human SYT4 regulated GSIS in EndoC-βH1 cells, a human β cell line. These findings reveal the role that altered Ca2+ sensing plays in regulating β cell maturation.

KEYWORDS:

Ca(2+); Myt1; Syt4; diabetes; docking; insulin; maturation; membrane fusion; secretion; vesicle

PMID:
29656931
PMCID:
PMC5962294
[Available on 2019-05-07]
DOI:
10.1016/j.devcel.2018.03.013
[Indexed for MEDLINE]

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