Adrenaline stimulates glucagon secretion by Tpc2-Dependent ca
            2+ mobilization from acidic stores in pancreatic a-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 ca ²⁺ mobilization from acidic stores in pancreatic a-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

Research output: Contribution to journal › Article › peer-review

83 Citations (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 in mouse and human a-cells by a combination of electrophysiology, imaging of Ca ²⁺ 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 [Ca ²⁺] _i in a-cells, which occurred without stimulation of electrical activity and persisted in the absence of extracellular Ca ²⁺ but was sensitive to ryanodine, bafilomycin, and thapsigargin. Adrenaline also increased [Ca ²⁺] _i in a-cells in human islets. Genetic or pharmacological inhibition of the Tpc2 channel (that mediates Ca ²⁺ release from acidic intracellular stores) abolished the stimulatory effect of adrenaline on glucagon secretion and reduced the elevation of [Ca ²⁺] _i. Furthermore, in Tpc2-deficient islets, ryanodine exerted no additive inhibitory effect. These data suggest that b-adrenergic stimulation of glucagon secretion is controlled by a hierarchy of [Ca ²⁺] _i signaling in the a-cell that is initiated by cAMP-induced Tpc2-dependent Ca ²⁺ release from the acidic stores and further amplified by Ca ²⁺-induced Ca ²⁺ release from the sarco/endoplasmic reticulum.

Original language	English
Pages (from-to)	1128-1139
Number of pages	12
Journal	Diabetes
Volume	67
Issue number	6
Early online date	21 May 2018
DOIs	https://doi.org/10.2337/db17-1102
Publication status	Published - 1 Jun 2018

Keywords

Adrenergic Neurons/cytology
Animals
Animals, Outbred Strains
Calcium Channels/chemistry
Calcium Signaling/drug effects
Cyclic AMP-Dependent Protein Kinases/antagonists & inhibitors
Endoplasmic Reticulum/drug effects
Enzyme Inhibitors/pharmacology
Epinephrine/metabolism
Glucagon/secretion
Glucagon-Secreting Cells/cytology
Guanine Nucleotide Exchange Factors/antagonists & inhibitors
Humans
Membrane Transport Modulators/pharmacology
Mice
Mice, Inbred C57BL
Mice, Knockout
Pancreas/drug effects
Patch-Clamp Techniques
Sarcoplasmic Reticulum/drug effects
Tissue Culture Techniques
Up-Regulation/drug effects

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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 ca ²⁺ mobilization from acidic stores in pancreatic a-Cells. Diabetes, 67(6), 1128-1139. https://doi.org/10.2337/db17-1102

@article{32466c3f4ace44328d993aeeccd4544d,

title = "Adrenaline stimulates glucagon secretion by Tpc2-Dependent ca 2+ mobilization from acidic stores in pancreatic a-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 in mouse and human a-cells by a combination of electrophysiology, imaging of Ca 2+ 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 [Ca 2+] i in a-cells, which occurred without stimulation of electrical activity and persisted in the absence of extracellular Ca 2+ but was sensitive to ryanodine, bafilomycin, and thapsigargin. Adrenaline also increased [Ca 2+] i in a-cells in human islets. Genetic or pharmacological inhibition of the Tpc2 channel (that mediates Ca 2+ release from acidic intracellular stores) abolished the stimulatory effect of adrenaline on glucagon secretion and reduced the elevation of [Ca 2+] i. Furthermore, in Tpc2-deficient islets, ryanodine exerted no additive inhibitory effect. These data suggest that b-adrenergic stimulation of glucagon secretion is controlled by a hierarchy of [Ca 2+] i signaling in the a-cell that is initiated by cAMP-induced Tpc2-dependent Ca 2+ release from the acidic stores and further amplified by Ca 2+-induced Ca 2+ release from the sarco/endoplasmic reticulum. ",

keywords = "Adrenergic Neurons/cytology, Animals, Animals, Outbred Strains, Calcium Channels/chemistry, Calcium Signaling/drug effects, Cyclic AMP-Dependent Protein Kinases/antagonists \& inhibitors, Endoplasmic Reticulum/drug effects, Enzyme Inhibitors/pharmacology, Epinephrine/metabolism, Glucagon/secretion, Glucagon-Secreting Cells/cytology, Guanine Nucleotide Exchange Factors/antagonists \& inhibitors, Humans, Membrane Transport Modulators/pharmacology, Mice, Mice, Inbred C57BL, Mice, Knockout, Pancreas/drug effects, Patch-Clamp Techniques, Sarcoplasmic Reticulum/drug effects, Tissue Culture Techniques, Up-Regulation/drug effects",

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\}",

note = "{\textcopyright} 2018 by the American Diabetes Association.",

year = "2018",

month = jun,

day = "1",

doi = "10.2337/db17-1102",

language = "English",

volume = "67",

pages = "1128--1139",

journal = "Diabetes",

issn = "0012-1797",

publisher = "American Diabetes Association Inc.",

number = "6",

}

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 ca ²⁺ mobilization from acidic stores in pancreatic a-Cells', Diabetes, vol. 67, no. 6, pp. 1128-1139. https://doi.org/10.2337/db17-1102

TY - JOUR

T1 - Adrenaline stimulates glucagon secretion by Tpc2-Dependent ca 2+ mobilization from acidic stores in pancreatic a-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 - 2018/6/1

Y1 - 2018/6/1

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 in mouse and human a-cells by a combination of electrophysiology, imaging of Ca 2+ 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 [Ca 2+] i in a-cells, which occurred without stimulation of electrical activity and persisted in the absence of extracellular Ca 2+ but was sensitive to ryanodine, bafilomycin, and thapsigargin. Adrenaline also increased [Ca 2+] i in a-cells in human islets. Genetic or pharmacological inhibition of the Tpc2 channel (that mediates Ca 2+ release from acidic intracellular stores) abolished the stimulatory effect of adrenaline on glucagon secretion and reduced the elevation of [Ca 2+] i. Furthermore, in Tpc2-deficient islets, ryanodine exerted no additive inhibitory effect. These data suggest that b-adrenergic stimulation of glucagon secretion is controlled by a hierarchy of [Ca 2+] i signaling in the a-cell that is initiated by cAMP-induced Tpc2-dependent Ca 2+ release from the acidic stores and further amplified by Ca 2+-induced Ca 2+ 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 in mouse and human a-cells by a combination of electrophysiology, imaging of Ca 2+ 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 [Ca 2+] i in a-cells, which occurred without stimulation of electrical activity and persisted in the absence of extracellular Ca 2+ but was sensitive to ryanodine, bafilomycin, and thapsigargin. Adrenaline also increased [Ca 2+] i in a-cells in human islets. Genetic or pharmacological inhibition of the Tpc2 channel (that mediates Ca 2+ release from acidic intracellular stores) abolished the stimulatory effect of adrenaline on glucagon secretion and reduced the elevation of [Ca 2+] i. Furthermore, in Tpc2-deficient islets, ryanodine exerted no additive inhibitory effect. These data suggest that b-adrenergic stimulation of glucagon secretion is controlled by a hierarchy of [Ca 2+] i signaling in the a-cell that is initiated by cAMP-induced Tpc2-dependent Ca 2+ release from the acidic stores and further amplified by Ca 2+-induced Ca 2+ release from the sarco/endoplasmic reticulum.

KW - Adrenergic Neurons/cytology

KW - Animals

KW - Animals, Outbred Strains

KW - Calcium Channels/chemistry

KW - Calcium Signaling/drug effects

KW - Cyclic AMP-Dependent Protein Kinases/antagonists & inhibitors

KW - Endoplasmic Reticulum/drug effects

KW - Enzyme Inhibitors/pharmacology

KW - Epinephrine/metabolism

KW - Glucagon/secretion

KW - Glucagon-Secreting Cells/cytology

KW - Guanine Nucleotide Exchange Factors/antagonists & inhibitors

KW - Humans

KW - Membrane Transport Modulators/pharmacology

KW - Mice

KW - Mice, Inbred C57BL

KW - Mice, Knockout

KW - Pancreas/drug effects

KW - Patch-Clamp Techniques

KW - Sarcoplasmic Reticulum/drug effects

KW - Tissue Culture Techniques

KW - Up-Regulation/drug effects

UR - https://www.scopus.com/pages/publications/85047739348

U2 - 10.2337/db17-1102

DO - 10.2337/db17-1102

M3 - Article

C2 - 29563152

SN - 0012-1797

VL - 67

SP - 1128

EP - 1139

JO - Diabetes

JF - Diabetes

IS - 6

ER -

Adrenaline stimulates glucagon secretion by Tpc2-Dependent ca ²⁺ mobilization from acidic stores in pancreatic a-Cells

Abstract

Keywords

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