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bioRxiv · 10.1101/2024.03.11.584397

The Kv2.2 channel mediates the inhibition of Prostaglandin E2 on glucose-stimulated insulin secretion in pancreatic β/-cells

Pan, C.·Liu, Y.·Wang, L.·Fan, W.-Y.·Ni, Y.·Zhang, X.·Wu, D.·Li, C.·Li, J.·Li, Z.·Liu, R.·Hu, C.
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Abstract

Prostaglandin E2 (PGE2) is an endogenous inhibitor of glucose-stimulated insulin secretion (GSIS) and plays an important role in pancreatic {beta}-cell dysfunction in type 2 diabetes mellitus (T2DM). This study aimed to explore the underlying mechanism by which PGE2 inhibits GSIS. Our results showed that PGE2 inhibited Kv2.2 channels via increasing PKA activity in HEK293T cells overexpressed with Kv2.2 channels. Point mutation analysis demonstrated that S448 residue was responsible for the PKA-dependent modulation of Kv2.2. Furthermore, the inhibitory effect of PGE2 on Kv2.2 was blocked by EP2/4 receptor antagonists, while mimicked by EP2/4 receptor agonists. The immune fluorescence results showed that EP1-EP4 receptors are expressed in both mouse and human {beta}-cells. In INS-1(832/13) {beta}-cells, PGE2 inhibited voltage-gated potassium currents and electrical activity through EP2/4 receptors and Kv2.2 channels. Knockdown of Kv2.2 reduced the action potential firing frequency and alleviated the inhibition of PGE2 on GSIS in INS-1(832/13) {beta}-cells. PGE2 impaired glucose tolerance in wild-type mice but did not alter glucose tolerance in Kv2.2 knockout mice. Knockout of Kv2.2 reduced electrical activity, GSIS and abrogated the inhibition of PGE2 on GSIS in mouse islets. In conclusion, we have demonstrated that PGE2 inhibits GSIS in pancreatic {beta}-cells through the EP2/4-Kv2.2 signaling pathway. The findings highlight the significant role of Kv2.2 channels in the regulation of {beta}-cell repetitive firing and insulin secretion, and contribute to the understanding of the molecular basis of {beta}-cell dysfunction in diabetes.

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Pan, C., Liu, Y., Wang, L., Fan, W.-Y., Ni, Y., Zhang, X., Wu, D., Li, C., Li, J., Li, Z., Liu, R., Hu, C.. 2024-03-13. The Kv2.2 channel mediates the inhibition of Prostaglandin E2 on glucose-stimulated insulin secretion in pancreatic β/-cells. https://doi.org/10.1101/2024.03.11.584397

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