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

Publication date: Available online 12 April 2018
Source:Developmental Cell
Author(s): Chen Huang, Emily M. Walker, Prasanna K. Dadi, Ruiying Hu, Yanwen Xu, Wenjian Zhang, Tiziana Sanavia, Jisoo Mun, Jennifer Liu, Gopika G. Nair, Hwee Yim Angeline Tan, Sui Wang, Mark A. Magnuson, Christian J. Stoeckert, Matthias Hebrok, Maureen Gannon, Weiping Han, Roland Stein, David A. Jacobson, Guoqiang Gu
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.

Graphical abstract

Teaser

In immature pancreatic beta cells, high glucose does not prompt an increase in insulin secretion. Huang et al. show that this poor response is due to greater Ca²⁺ sensitivity in immature cells, producing a higher basal secretion rate. Furthermore, Ca²⁺ sensitivity is regulated by synaptotagmin 4, whose levels increase during maturation.


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