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Journal of Physiology-London

Journal of Physiology-London

IF: 4.7
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TRPV4 couples with NCX1 to mediate glucose‐dependent glucagon‐like peptide‐1 release and improve glucose homeostasis

Published:21 November 2024 DOI: 10.1113/jp287092 PMID: 39573816
Xiongying Chen, Fenglan Chu, Sijin Sunchen, Junhui Li, Mengting Zhang, Feng Xu, Hui Dong

Abstract

Although glucose, as a secretagogue of intestinal hormone, can stimulate glucagon-like peptide 1 (GLP-1) release, it has not been fully elucidated how glucose triggers GLP-1 release from enteroendocrine cells (EECs). Here, we investigated the regulatory mechanisms of glucose-induced Ca2+-dependent GLP-1 release from EECs. STC-1 cells that possess many features of native intestinal EECs were used. The expression of TRPV4 channels and Na+/Ca2+ exchanger 1 (NCX1) in STC-1 was analysed by immunocytochemistry. Calcium and sodium imaging, and patch clamp were applied, and GLP-1 was detected using quantitative PCR, western blot and enzyme-linked immunosorbent assays. Glucose markedly induced Na+ and Ca2+ signalling in STC-1 cells. The glucose-induced Ca2+ signalling was significantly attenuated by selective blockers of the voltage-gated Ca2+ channels (VGCC), ryanodine receptors and InsP3 receptors. Most importantly, glucose-induced Ca2+ signalling was significantly attenuated by the selective blockers of TRPV4 and NCX1. Moreover, the physical and functional couplings of TRPV4 and NCX1 were demonstrated in STC-1 cells, and they promoted glucose-mediated Ca2+ signalling to upregulate expression and release of GLP-1 via Ca2+-sensitive PKCα. Finally, the selective TRPV4 activator improved glucose tolerance in an oral glucose tolerance test in mice, but the selective blockers of TRPV4 and NCX1 attenuated glucose-induced intestinal GLP-1 release. We demonstrate a coupling of TRPV4 and NCX1 in EECs to regulate glucose-stimulated intestinal GLP-1 release via a novel TRPV4/NCX1/Ca2+/PKCα axis. Targeting this axis may provide new therapeutic potentials for glycometabolic diseases. KEY POINTS: Glucagon-like peptide 1 (GLP-1) secreted primarily from intestinal L cells in response to meals plays a critical role in maintaining glucose homeostasis. Physical and functional couplings of TRPV4 and NCX1 are pivotal in glucose-stimulated GLP-1 release via a novel TRPV4/NCX1/Ca2+/PKCα axis. Since this axis is involved in glucose homeostasis, our findings may provide new potential drug targets for prevention/treatment of glycometabolic diseases.

Substances (8)

Materials
Procduct Name CAS Molecular Formula Supplier Price
Calcium chloride 10043-52-4 CaCl2 1213 suppliers $5.00-$26371.00
D-Mannitol 69-65-8 C6H14O6 1026 suppliers $5.00-$6490.00
BAPTA-AM 126150-97-8 C34H40N2O18 233 suppliers $13.00-$1530.00
TPEN 16858-02-9 C26H28N6 195 suppliers $9.00-$4200.00
GO 6976 136194-77-9 C24H18N4O 168 suppliers $42.00-$3900.00
Nicardipine 55985-32-5 C26H29N3O6 152 suppliers $16.00-$3265.94
N-((S)-1-(4-((S)-2-(2,4-dichlorophenylsulfonaMido)-3-hydroxypropanoyl)piperazin-1-yl)-4-Methyl-1-oxopentan-2-yl)benzo[b]thiophene-2-carboxaMide 942206-85-1 C28H32Cl2N4O6S2 115 suppliers $15.00-$2700.00
FETUIN 9014-81-7 NULL 92 suppliers $37.07-$4810.00

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