Syntaxin-4 mediates exocytosis of pre-docked and newcomer insulin granules underlying biphasic glucose-stimulated insulin secretion in human pancreatic beta cells

Diabetologia
L XieHerbert Y Gaisano

Abstract

Of the four exocytotic syntaxins (Syns), much is now known about the role of Syn-1A (pre-docked secretory granules [SGs]) and Syn-3 (newcomer SGs) in insulin exocytosis. Some work was reported on Syn-4's role in biphasic glucose-stimulated insulin secretion (GSIS), but its precise role in insulin SG exocytosis remains unclear. In this paper we examine this role in human beta cells. Endogenous function of Syn-4 in human islets was assessed by knocking down its expression with lentiviral single hairpin RNA (lenti-shRNA)-RFP. Biphasic GSIS was determined by islet perifusion assay. Single-cell analysis of exocytosis of red fluorescent protein (RFP)-positive beta cells (exhibiting near-total depletion of Syn-4) was by patch clamp capacitance measurements (Cm) and total internal reflection fluorescence microscopy (TIRFM), the latter to further assess single SG behaviour. Co-immunoprecipitations were conducted on INS-1 cells to assess exocytotic complexes. Syn-4 knockdown (KD) of 77% in human islets caused a concomitant reduction in cognate Munc18c expression (46%) without affecting expression of other exocytotic proteins; this resulted in reduction of GSIS in the first phase (by 42%) and the second phase (by 40%). Cm of RFP-tagged Sy...Continue Reading

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Citations

Oct 5, 2016·The Journal of Cell Biology·Masataka KuniiAkihiro Harada
Jan 25, 2017·Diabetes·Dan ZhuHerbert Y Gaisano
Mar 23, 2017·Cell Structure and Function·Hitomi SatoKenji Kohno
Apr 18, 2018·Diabetes·Arianne AslamyDebbie C Thurmond
Dec 30, 2016·The Journal of Biological Chemistry·Tao LiangHerbert Y Gaisano
Dec 22, 2019·Journal of Molecular Biology·Debbie C Thurmond, Herbert Y Gaisano
Mar 7, 2021·International Journal of Molecular Sciences·Diti Chatterjee BhowmickDebbie C Thurmond
Jun 10, 2021·American Journal of Physiology. Cell Physiology·David D Roberts, Jeffrey S Isenberg

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