Loss of tetraspanin-7 expression reduces pancreatic β-cell exocytosis Ca2+ sensitivity but has limited effect on systemic metabolism
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Background: Tetraspanin-7 (Tspan7) is an islet autoantigen involved in autoimmune type 1 diabetes and known to regulate beta-cell L-type Ca-2(+) channel activity. However, the role of Tspan7 in pancreatic beta-cell function is not yet fully understood.
Methods: Histological analyses were conducted using immunostaining. Whole-body metabolism was tested using glucose tolerance test. Islet hormone secretion was quantified using static batch incubation or dynamic perifusion. beta-cell transmembrane currents, electrical activity and exocytosis were measured using whole-cell patch-clamping and capacitance measurements. Gene expression was studied using m RNA-sequencing and quantitative PCR.
Results: Tspan7 is expressed in insulin-containing granules of pancreatic beta-cells and glucagon-producing alpha-cells. Tspan7 knockout mice (Tspan(gamma/-) mouse) exhibit reduced body weight and ad libitum plasma glucose but normal glucose tolerance. Tspan(gamma/- )islets have normal insulin content and glucose- or tolbutamide-stimulated insulin secretion. Depolarisation-triggered Ca2+ current was enhanced in Tspan(gamma/-) beta-cells, but beta-cell electrical activity and depolarisation-evoked exocytosis were unchanged suggesting that exocytosis was less sensitive to Ca2+. TSPAN7 knockdown (KD) in human pseudo-islets led to a significant reduction in insulin secretion stimulated by 20 mM Transcriptomic analyses show that TSPAN7 KD in human pseudo-islets correlated with changes in genes involved in hormone secretion, apoptosis and ER stress. Consistent with rodent beta-cells, exocytotic Ca2+ sensitivity was reduced in a human beta-cell line (EndoC-beta H1) following Tspan7 KD.
Conclusion: Tspan7 is involved in the regulation of Ca2+-dependent exocytosis in beta-cells. Its function is more significant in human beta-cells than their rodent counterparts.
Original language | English |
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Article number | e14984 |
Journal | Diabetic Medicine |
Volume | 39 |
Issue number | 12 |
Number of pages | 13 |
ISSN | 0742-3071 |
DOIs | |
Publication status | Published - 2022 |
- beta-cell, exocytosis, insulin, synaptotagmin, tetraspanin-7, EXTRACELLULAR DOMAIN, SUPERFAMILY, GENE
Research areas
ID: 325837046