The highly expressed calcium‐insensitive synaptotagmin‐11 and synaptotagmin‐13 modulate insulin secretion. (2nd July 2022)

• Record Type: Journal Article
• Authors: Ofori, Jones K.; Karagiannopoulos, Alexandros; Barghouth, Mohammad; Nagao, Mototsugu; Andersson, Markus E.; Salunkhe, Vishal A.; Zhang, Enming; Wendt, Anna; Eliasson, Lena
• Is Part Of: Acta physiologica. Volume 236:Number 1(2022)
• Page Start: n/a
• Page End: n/a
• Publication Date: 2022-07-02
• Subjects: diabetes -- exocytosis -- insulin secretion -- islet -- synaptotagmin -- type‐2 diabetes; Physiology -- Periodicals; Physiology -- Research -- Periodicals; 612
• DOI: 10.1111/apha.13857
• Languages: English
• ISSNs: 1748-1708

Abstract

Abstract: Aim: SYT11 and SYT13, two calcium‐insensitive synaptotagmins, are downregulated in islets from type 2 diabetic donors, but their function in insulin secretion is unknown. To address this, we investigated the physiological role of these two synaptotagmins in insulin‐secreting cells. Methods: Correlations between gene expression levels were performed using previously described RNA‐seq data on islets from 188 human donors. SiRNA knockdown was performed in EndoC‐βH1 and INS‐1 832/13 cells. Insulin secretion was measured with ELISA. Patch‐clamp was used for single‐cell electrophysiology. Confocal microscopy was used to determine intracellular localization. Results: Human islet expression of the transcription factor PDX1 was positively correlated with SYT11 ( p = 2.4e −10 ) and SYT13 ( p < 2.2e −16 ). Syt11 and Syt13 both co‐localized with insulin, indicating their localization in insulin granules. Downregulation of Syt11 in INS‐1 832/13 cells (siSYT11) resulted in increased basal and glucose‐induced insulin secretion. Downregulation of Syt13 (siSYT13) decreased insulin secretion induced by glucose and K + . Interestingly, the cAMP‐raising agent forskolin was unable to enhance insulin secretion in siSYT13 cells. There was no difference in insulin content, exocytosis, or voltage‐gated Ca 2+ currents in the two models. Double knockdown of Syt11 and Syt13 (DKD) resembled the results in siSYT13 cells. Conclusion: SYT11 and SYT13 have similar localization and transcriptional regulation, but they regulate insulin secretion differentially. While downregulation of SYT11 might be a compensatory mechanism in type‐2 diabetes, downregulation of SYT13 reduces the insulin secretory response and overrules the compensatory regulation of SYT11 in a way that could aggravate the disease.