Adrenaline stimulates glucagon secretion by Tpc2-dependent Ca2+ mobilization from acidic stores in pancreatic α-cells
Adrenaline is a powerful stimulus of glucagon secretion. It acts by activation of β-adrenergic receptors but the downstream mechanisms have only been partially elucidated. Here we have examined the effects of adrenaline in mouse and human α-cells by a combination of electrophysiology, imaging of Ca2...
| Main Authors: | , , , , , , , , , , , , , , , , |
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| Format: | Journal article |
| Language: | English |
| Published: |
American Diabetes Association
2018
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| _version_ | 1826306208806469632 |
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| author | Hamilton, A Zhang, Q Salehi, A Willems, M Knudsen, JG Ringgaard, AK Chapman, CE Gonzalez-Alvarez, A Surdo, NC Zaccolo, M Basco, D Johnson, PRV Ramracheya, RD Rutter, GA Galione, A Rorsman, P Tarasov, AI |
| author_facet | Hamilton, A Zhang, Q Salehi, A Willems, M Knudsen, JG Ringgaard, AK Chapman, CE Gonzalez-Alvarez, A Surdo, NC Zaccolo, M Basco, D Johnson, PRV Ramracheya, RD Rutter, GA Galione, A Rorsman, P Tarasov, AI |
| author_sort | Hamilton, A |
| collection | OXFORD |
| description | Adrenaline is a powerful stimulus of glucagon secretion. It acts by activation of β-adrenergic receptors but the downstream mechanisms have only been partially elucidated. Here we have examined the effects of adrenaline in mouse and human α-cells by a combination of electrophysiology, imaging of Ca2+ and PKA activity and hormone release measurements. We found that stimulation of glucagon secretion correlated with a PKA- and EPAC2-dependent (inhibited by PKI and ESI-05, respectively) elevation of [Ca2+]i in α-cells, which occurred without stimulation of electrical activity, persisted in the absence of extracellular Ca2+ but was sensitive to ryanodine, bafilomycin and thapsigargin. Adrenaline also increased [Ca2+]i in α-cells in human islets. Genetic or pharmacological inhibition of Tpc2 channel (that mediates Ca2+ release from acidic intracellular stores) abolished the stimulatory effect of adrenaline on glucagon secretion and reduced the elevation of [Ca2+]i. Furthermore, in Tpc2-deficient islets, ryanodine exerted no additive inhibitory effect. These data suggest that β-adrenergic stimulation of glucagon secretion is controlled by a hierarchy of [Ca2+]i signaling in the α-cell that is initiated by cAMP-induced Tpc2-dependent Ca2+ release from the acidic stores and further amplified by Ca2+-induced Ca2+ release from the sarco/endoplasmic reticulum. |
| first_indexed | 2024-03-07T06:44:27Z |
| format | Journal article |
| id | oxford-uuid:fa63526b-c205-4ea7-a098-5ee61b5181b5 |
| institution | University of Oxford |
| language | English |
| last_indexed | 2024-03-07T06:44:27Z |
| publishDate | 2018 |
| publisher | American Diabetes Association |
| record_format | dspace |
| spelling | oxford-uuid:fa63526b-c205-4ea7-a098-5ee61b5181b52022-03-27T13:05:33ZAdrenaline stimulates glucagon secretion by Tpc2-dependent Ca2+ mobilization from acidic stores in pancreatic α-cellsJournal articlehttp://purl.org/coar/resource_type/c_dcae04bcuuid:fa63526b-c205-4ea7-a098-5ee61b5181b5EnglishSymplectic Elements at OxfordAmerican Diabetes Association2018Hamilton, AZhang, QSalehi, AWillems, MKnudsen, JGRinggaard, AKChapman, CEGonzalez-Alvarez, ASurdo, NCZaccolo, MBasco, DJohnson, PRVRamracheya, RDRutter, GAGalione, ARorsman, PTarasov, AIAdrenaline is a powerful stimulus of glucagon secretion. It acts by activation of β-adrenergic receptors but the downstream mechanisms have only been partially elucidated. Here we have examined the effects of adrenaline in mouse and human α-cells by a combination of electrophysiology, imaging of Ca2+ and PKA activity and hormone release measurements. We found that stimulation of glucagon secretion correlated with a PKA- and EPAC2-dependent (inhibited by PKI and ESI-05, respectively) elevation of [Ca2+]i in α-cells, which occurred without stimulation of electrical activity, persisted in the absence of extracellular Ca2+ but was sensitive to ryanodine, bafilomycin and thapsigargin. Adrenaline also increased [Ca2+]i in α-cells in human islets. Genetic or pharmacological inhibition of Tpc2 channel (that mediates Ca2+ release from acidic intracellular stores) abolished the stimulatory effect of adrenaline on glucagon secretion and reduced the elevation of [Ca2+]i. Furthermore, in Tpc2-deficient islets, ryanodine exerted no additive inhibitory effect. These data suggest that β-adrenergic stimulation of glucagon secretion is controlled by a hierarchy of [Ca2+]i signaling in the α-cell that is initiated by cAMP-induced Tpc2-dependent Ca2+ release from the acidic stores and further amplified by Ca2+-induced Ca2+ release from the sarco/endoplasmic reticulum. |
| spellingShingle | Hamilton, A Zhang, Q Salehi, A Willems, M Knudsen, JG Ringgaard, AK Chapman, CE Gonzalez-Alvarez, A Surdo, NC Zaccolo, M Basco, D Johnson, PRV Ramracheya, RD Rutter, GA Galione, A Rorsman, P Tarasov, AI Adrenaline stimulates glucagon secretion by Tpc2-dependent Ca2+ mobilization from acidic stores in pancreatic α-cells |
| title | Adrenaline stimulates glucagon secretion by Tpc2-dependent Ca2+ mobilization from acidic stores in pancreatic α-cells |
| title_full | Adrenaline stimulates glucagon secretion by Tpc2-dependent Ca2+ mobilization from acidic stores in pancreatic α-cells |
| title_fullStr | Adrenaline stimulates glucagon secretion by Tpc2-dependent Ca2+ mobilization from acidic stores in pancreatic α-cells |
| title_full_unstemmed | Adrenaline stimulates glucagon secretion by Tpc2-dependent Ca2+ mobilization from acidic stores in pancreatic α-cells |
| title_short | Adrenaline stimulates glucagon secretion by Tpc2-dependent Ca2+ mobilization from acidic stores in pancreatic α-cells |
| title_sort | adrenaline stimulates glucagon secretion by tpc2 dependent ca2 mobilization from acidic stores in pancreatic α cells |
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