Loss of tetraspanin-7 expression reduces pancreatic β-cell exocytosis Ca2+ sensitivity but has limited effect on systemic metabolism
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Loss of tetraspanin-7 expression reduces pancreatic β-cell exocytosis Ca2+ sensitivity but has limited effect on systemic metabolism. / McLaughlin, Kerry; Acreman, Samuel; Nawaz, Sameena; Cutteridge, Joseph; Clark, Anne; Knudsen, Jakob G.; Denwood, Geoffrey; Spigelman, Aliya F.; Fox, Jocelyn E. Manning; Singh, Sumeet Pal; MacDonald, Patrick E.; Hastoy, Benoit; Zhang, Quan.
I: Diabetic Medicine, Bind 39, Nr. 12, e14984, 2022.Publikation: Bidrag til tidsskrift › Tidsskriftartikel › Forskning › fagfællebedømt
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T1 - Loss of tetraspanin-7 expression reduces pancreatic β-cell exocytosis Ca2+ sensitivity but has limited effect on systemic metabolism
AU - McLaughlin, Kerry
AU - Acreman, Samuel
AU - Nawaz, Sameena
AU - Cutteridge, Joseph
AU - Clark, Anne
AU - Knudsen, Jakob G.
AU - Denwood, Geoffrey
AU - Spigelman, Aliya F.
AU - Fox, Jocelyn E. Manning
AU - Singh, Sumeet Pal
AU - MacDonald, Patrick E.
AU - Hastoy, Benoit
AU - Zhang, Quan
PY - 2022
Y1 - 2022
N2 - 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.
AB - 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.
KW - beta-cell
KW - exocytosis
KW - insulin
KW - synaptotagmin
KW - tetraspanin-7
KW - EXTRACELLULAR DOMAIN
KW - SUPERFAMILY
KW - GENE
U2 - 10.1111/dme.14984
DO - 10.1111/dme.14984
M3 - Journal article
C2 - 36264270
VL - 39
JO - Diabetic Medicine
JF - Diabetic Medicine
SN - 0742-3071
IS - 12
M1 - e14984
ER -
ID: 325837046