Adrenaline Stimulates Glucagon Secretion by Tpc2-Dependent Ca2+ Mobilization From Acidic Stores in Pancreatic α-Cells

Alexander Hamilton; Quan Zhang; Albert Salehi; Mara Willems; Jakob G. Knudsen; Anna K. Ringgaard; Caroline E. Chapman; Alejandro Gonzalez-Alvarez; Nicoletta C. Surdo; Manuela Zaccolo; Davide Basco; Paul R. V. Johnson; Reshma Ramracheya; Guy A. Rutter; Antony Galione; Patrik Rorsman; Andrei I. Tarasov

doi:10.2337/db17-1102

Adrenaline Stimulates Glucagon Secretion by Tpc2-Dependent Ca²⁺ Mobilization From Acidic Stores in Pancreatic α-Cells

Alexander Hamilton, Quan Zhang, Albert Salehi, Mara Willems, Jakob G. Knudsen, Anna K. Ringgaard, Caroline E. Chapman, Alejandro Gonzalez-Alvarez, Nicoletta C. Surdo, Manuela Zaccolo, Davide Basco, Paul R. V. Johnson, Reshma Ramracheya, Guy A. Rutter, Antony Galione, Patrik Rorsman, Andrei I. Tarasov

Biomedicinsk Institut

Publikation: Bidrag til tidsskrift › Tidsskriftartikel › Forskning › peer review

76 Citationer (Scopus)

Abstract

Adrenaline is a powerful stimulus of glucagon secretion. It acts by activation of b-adrenergic receptors, but the downstream mechanisms have only been partially elucidated. Here, we have examined the effects of adrenaline inmouse and human alpha-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 alpha-cells, which occurred without stimulation of electrical activity and persisted in the absence of extracellular Ca2+ but was sensitive to ryanodine, bafilomycin, and thapsigargin. Adrenaline also increased [Ca2+](i) in alpha-cells in human islets. Genetic or pharmacological inhibition of the 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 thatb-adrenergic stimulation of glucagon secretion is controlled by a hierarchy of [Ca2+](i) signaling in the alpha-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.

Originalsprog	Engelsk
Tidsskrift	Diabetes
Vol/bind	67
Udgave nummer	6
Sider (fra-til)	1128-1139
ISSN	0012-1797
DOI	https://doi.org/10.2337/db17-1102
Status	Udgivet - 2018

Adgang til dokumentet

10.2337/db17-1102

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6258900/pdf/emss-80476.pdfLicens: Andet

Citationsformater

Hamilton, A., Zhang, Q., Salehi, A., Willems, M., Knudsen, J. G., Ringgaard, A. K., Chapman, C. E., Gonzalez-Alvarez, A., Surdo, N. C., Zaccolo, M., Basco, D., Johnson, P. R. V., Ramracheya, R., Rutter, G. A., Galione, A., Rorsman, P., & Tarasov, A. I. (2018). Adrenaline Stimulates Glucagon Secretion by Tpc2-Dependent Ca²⁺ Mobilization From Acidic Stores in Pancreatic α-Cells. Diabetes, 67(6), 1128-1139. https://doi.org/10.2337/db17-1102

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, R, Rutter, GA, Galione, A, Rorsman, P & Tarasov, AI 2018, 'Adrenaline Stimulates Glucagon Secretion by Tpc2-Dependent Ca²⁺ Mobilization From Acidic Stores in Pancreatic α-Cells', Diabetes, bind 67, nr. 6, s. 1128-1139. https://doi.org/10.2337/db17-1102

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title = "Adrenaline Stimulates Glucagon Secretion by Tpc2-Dependent Ca2+ Mobilization From Acidic Stores in Pancreatic α-Cells",

abstract = "Adrenaline is a powerful stimulus of glucagon secretion. It acts by activation of b-adrenergic receptors, but the downstream mechanisms have only been partially elucidated. Here, we have examined the effects of adrenaline inmouse and human alpha-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 alpha-cells, which occurred without stimulation of electrical activity and persisted in the absence of extracellular Ca2+ but was sensitive to ryanodine, bafilomycin, and thapsigargin. Adrenaline also increased [Ca2+](i) in alpha-cells in human islets. Genetic or pharmacological inhibition of the 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 thatb-adrenergic stimulation of glucagon secretion is controlled by a hierarchy of [Ca2+](i) signaling in the alpha-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.",

author = "Alexander Hamilton and Quan Zhang and Albert Salehi and Mara Willems and Knudsen, {Jakob G.} and Ringgaard, {Anna K.} and Chapman, {Caroline E.} and Alejandro Gonzalez-Alvarez and Surdo, {Nicoletta C.} and Manuela Zaccolo and Davide Basco and Johnson, {Paul R. V.} and Reshma Ramracheya and Rutter, {Guy A.} and Antony Galione and Patrik Rorsman and Tarasov, {Andrei I.}",

year = "2018",

doi = "10.2337/db17-1102",

language = "English",

volume = "67",

pages = "1128--1139",

journal = "Diabetes",

issn = "0012-1797",

publisher = "American Diabetes Association",

number = "6",

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TY - JOUR

T1 - Adrenaline Stimulates Glucagon Secretion by Tpc2-Dependent Ca2+ Mobilization From Acidic Stores in Pancreatic α-Cells

AU - Hamilton, Alexander

AU - Zhang, Quan

AU - Salehi, Albert

AU - Willems, Mara

AU - Knudsen, Jakob G.

AU - Ringgaard, Anna K.

AU - Chapman, Caroline E.

AU - Gonzalez-Alvarez, Alejandro

AU - Surdo, Nicoletta C.

AU - Zaccolo, Manuela

AU - Basco, Davide

AU - Johnson, Paul R. V.

AU - Ramracheya, Reshma

AU - Rutter, Guy A.

AU - Galione, Antony

AU - Rorsman, Patrik

AU - Tarasov, Andrei I.

PY - 2018

Y1 - 2018

N2 - Adrenaline is a powerful stimulus of glucagon secretion. It acts by activation of b-adrenergic receptors, but the downstream mechanisms have only been partially elucidated. Here, we have examined the effects of adrenaline inmouse and human alpha-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 alpha-cells, which occurred without stimulation of electrical activity and persisted in the absence of extracellular Ca2+ but was sensitive to ryanodine, bafilomycin, and thapsigargin. Adrenaline also increased [Ca2+](i) in alpha-cells in human islets. Genetic or pharmacological inhibition of the 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 thatb-adrenergic stimulation of glucagon secretion is controlled by a hierarchy of [Ca2+](i) signaling in the alpha-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.

AB - Adrenaline is a powerful stimulus of glucagon secretion. It acts by activation of b-adrenergic receptors, but the downstream mechanisms have only been partially elucidated. Here, we have examined the effects of adrenaline inmouse and human alpha-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 alpha-cells, which occurred without stimulation of electrical activity and persisted in the absence of extracellular Ca2+ but was sensitive to ryanodine, bafilomycin, and thapsigargin. Adrenaline also increased [Ca2+](i) in alpha-cells in human islets. Genetic or pharmacological inhibition of the 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 thatb-adrenergic stimulation of glucagon secretion is controlled by a hierarchy of [Ca2+](i) signaling in the alpha-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.

U2 - 10.2337/db17-1102

DO - 10.2337/db17-1102

M3 - Journal article

C2 - 29563152

SN - 0012-1797

VL - 67

SP - 1128

EP - 1139

JO - Diabetes

JF - Diabetes

IS - 6

ER -