The TCF7L2-dependent high-voltage activated calcium channel subunit α2δ-1 controls calcium signaling in rodent pancreatic beta-cells. (15th February 2020)

• Record Type: Journal Article
• Authors: Ye, Yingying; Barghouth, Mohammad; Luan, Cheng; Kazim, Abdulla; Zhou, Yuedan; Eliasson, Lena; Zhang, Enming; Hansson, Ola; Thevenin, Thomas; Renström, Erik
• Is Part Of: Molecular and cellular endocrinology. Volume 502(2020)
• Publication Date: 2020-02-15
• Subjects: Tcf7l2 -- α2δ-1 -- Type 2 diabetes; Endocrinology -- Periodicals; Molecular biology -- Periodicals; Cytology -- Periodicals; Endocrinology -- Periodicals; Hormones -- Periodicals; Endocrinologie -- Périodiques; Cytology; Endocrinology; Molecular biology; Periodicals; 573.4
• DOI: 10.1016/j.mce.2019.110673
• Languages: English
• ISSNs: 0303-7207

Abstract

Abstract: The transcription factor TCF7L2 remains the most important diabetes gene identified to date and genetic risk carriers exhibit lower insulin secretion. We show that Tcf7l2 regulates the auxiliary subunit of voltage-gated Ca 2+ channels, Cacna2d1 gene/α2δ-1 protein levels. Furthermore, suppression of α2δ-1 decreased voltage-gated Ca 2+ currents and high glucose/depolarization-evoked Ca 2+ signaling which mimicked the effect of silencing of Tcf7l2 . This appears to be the result of impaired voltage-gated Ca 2+ channel trafficking to the plasma membrane, as Cav1.2 channels accumulated in the recycling endosomes after α2δ-1 suppression, in clonal as well as primary rodent beta-cells. This impaired the capacity for glucose-induced insulin secretion in Cacna2d1 -silenced cells. Overexpression of α2δ-1 increased high-glucose/K + -stimulated insulin secretion. Furthermore, overexpression of α2δ-1 in Tcf7l2 -silenced cells rescued the Tcf7l2 -dependent impairment of Ca 2+ signaling, but not the reduced insulin secretion. Taken together, these data clarify the connection between Tcf7l2, α2δ-1 in Ca 2+ -dependent insulin secretion. Graphical abstract: Image 1 Highlights: Tcf7l2 controls expression of Cacna2d1 /α2δ-1. Silencing of Cacna2d1 prevents trafficking of Cav1.2 to the plasma membrane. Silencing of Cacna2d1 retains Cav1.2 in recycling endosomes. Silencing of Cacna2d1 affects Ca 2+ signaling and exocytosis. Overexpression of α2δ-1 partially counteracts the effect of Tcf7l2 silencing.