Synaptotagmin 4 Regulates Pancreatic β Cell Maturation by Modulating the Ca 2+ Sensitivity of Insulin Secretion Vesicles

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

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Biological Transport
  • Calcium / pharmacology*
  • Cell Differentiation / drug effects
  • Female
  • Gene Expression Regulation / drug effects
  • Glucose / pharmacology*
  • Humans
  • Hypoglycemic Agents / metabolism
  • Insulin / metabolism*
  • Insulin Secretion
  • Insulin-Secreting Cells / cytology*
  • Insulin-Secreting Cells / drug effects
  • Insulin-Secreting Cells / metabolism
  • Male
  • Mice
  • Mice, Knockout
  • Sweetening Agents / pharmacology
  • Synaptotagmins / genetics
  • Synaptotagmins / metabolism*

Substances

  • Hypoglycemic Agents
  • Insulin
  • Sweetening Agents
  • Synaptotagmins
  • Glucose
  • Calcium