SUR1 regulates PKA-independent cAMP-induced granule priming in mouse pancreatic b-cells

Lena Eliasson, Xiaosong Ma, Erik Renström, Sebastian Barg, Per Olof Berggren, Juris Galvanovskis, Jesper Gromada, Xingjun Jing, Ingmar Lundquist, Albert Salehi, Sabine Sewing, Patrik Rorsman

Research output: Contribution to journalArticle

205 Citations (Scopus)

Abstract

Measurements of membrane capacitance were applied to dissect the cellular mechanisms underlying PKA-dependent and -independent stimulation of insulin secretion by cyclic AMP. Whereas the PKA-independent (Rp-cAMPS-insensitive) component correlated with a rapid increase in membrane capacitance of ∼80 fF that plateaued within ∼200 ms, the PKA-dependent component became prominent during depolarizations >450 ms. The PKA-dependent and -independent components of cAMP-stimulated exocytosis differed with regard to cAMP concentration dependence; the Kd values were 6 and 29 μM for the PKA-dependent and -independent mechanisms, respectively. The ability of cAMP to elicit exocytosis independently of PKA activation was mimicked by the selective cAMP-GEFII agonist 8CPT-2Me-cAMP. Moreover, treatment of B-cells with antisense oligodeoxynucleotides against cAMP-GEFII resulted in partial (50%) suppression of PKA-independent exocytosis. Surprisingly, B-cells in islets isolated from SUR1-deficient mice (SUR1-/- mice) lacked the PKA-independent component of exocytosis. Measurements of insulin release in response to GLP-1 stimulation in isolated islets from SUR1-/- mice confirmed the complete loss of the PKA-independent component. This was not attributable to a reduced capacity of GLP-1 to elevate intracellular cAMP but instead associated with the inability of cAMP to stimulate influx of Cl- into the granules, a step important for granule priming. We conclude that the role of SUR1 in the B cell extends beyond being a subunit of the plasma membrane KATP-channel and that it also plays an unexpected but important role in the cAMP-dependent regulation of Ca2+-induced exocytosis.

Original languageEnglish
Pages (from-to)181-197
Number of pages17
JournalJournal of General Physiology
Volume121
Issue number3
DOIs
StatePublished - Mar 1 2003
Externally publishedYes

Fingerprint

Exocytosis
Glucagon-Like Peptide 1
B-Lymphocytes
Insulin
KATP Channels
Membranes
Oligodeoxyribonucleotides
Ion Channels
Cyclic AMP
Cell Membrane

Keywords

  • Ca
  • CAMP
  • CAMP-GEFII
  • Insulin
  • SUR1

ASJC Scopus subject areas

  • Physiology

Cite this

Eliasson, L., Ma, X., Renström, E., Barg, S., Berggren, P. O., Galvanovskis, J., ... Rorsman, P. (2003). SUR1 regulates PKA-independent cAMP-induced granule priming in mouse pancreatic b-cells. Journal of General Physiology, 121(3), 181-197. https://doi.org/10.1085/jgp.20028707

SUR1 regulates PKA-independent cAMP-induced granule priming in mouse pancreatic b-cells. / Eliasson, Lena; Ma, Xiaosong; Renström, Erik; Barg, Sebastian; Berggren, Per Olof; Galvanovskis, Juris; Gromada, Jesper; Jing, Xingjun; Lundquist, Ingmar; Salehi, Albert; Sewing, Sabine; Rorsman, Patrik.

In: Journal of General Physiology, Vol. 121, No. 3, 01.03.2003, p. 181-197.

Research output: Contribution to journalArticle

Eliasson, L, Ma, X, Renström, E, Barg, S, Berggren, PO, Galvanovskis, J, Gromada, J, Jing, X, Lundquist, I, Salehi, A, Sewing, S & Rorsman, P 2003, 'SUR1 regulates PKA-independent cAMP-induced granule priming in mouse pancreatic b-cells', Journal of General Physiology, vol. 121, no. 3, pp. 181-197. https://doi.org/10.1085/jgp.20028707
Eliasson L, Ma X, Renström E, Barg S, Berggren PO, Galvanovskis J et al. SUR1 regulates PKA-independent cAMP-induced granule priming in mouse pancreatic b-cells. Journal of General Physiology. 2003 Mar 1;121(3):181-197. https://doi.org/10.1085/jgp.20028707
Eliasson, Lena ; Ma, Xiaosong ; Renström, Erik ; Barg, Sebastian ; Berggren, Per Olof ; Galvanovskis, Juris ; Gromada, Jesper ; Jing, Xingjun ; Lundquist, Ingmar ; Salehi, Albert ; Sewing, Sabine ; Rorsman, Patrik. / SUR1 regulates PKA-independent cAMP-induced granule priming in mouse pancreatic b-cells. In: Journal of General Physiology. 2003 ; Vol. 121, No. 3. pp. 181-197.
@article{cf470152e92b40c3aedba961732fe0b4,
title = "SUR1 regulates PKA-independent cAMP-induced granule priming in mouse pancreatic b-cells",
abstract = "Measurements of membrane capacitance were applied to dissect the cellular mechanisms underlying PKA-dependent and -independent stimulation of insulin secretion by cyclic AMP. Whereas the PKA-independent (Rp-cAMPS-insensitive) component correlated with a rapid increase in membrane capacitance of ∼80 fF that plateaued within ∼200 ms, the PKA-dependent component became prominent during depolarizations >450 ms. The PKA-dependent and -independent components of cAMP-stimulated exocytosis differed with regard to cAMP concentration dependence; the Kd values were 6 and 29 μM for the PKA-dependent and -independent mechanisms, respectively. The ability of cAMP to elicit exocytosis independently of PKA activation was mimicked by the selective cAMP-GEFII agonist 8CPT-2Me-cAMP. Moreover, treatment of B-cells with antisense oligodeoxynucleotides against cAMP-GEFII resulted in partial (50{\%}) suppression of PKA-independent exocytosis. Surprisingly, B-cells in islets isolated from SUR1-deficient mice (SUR1-/- mice) lacked the PKA-independent component of exocytosis. Measurements of insulin release in response to GLP-1 stimulation in isolated islets from SUR1-/- mice confirmed the complete loss of the PKA-independent component. This was not attributable to a reduced capacity of GLP-1 to elevate intracellular cAMP but instead associated with the inability of cAMP to stimulate influx of Cl- into the granules, a step important for granule priming. We conclude that the role of SUR1 in the B cell extends beyond being a subunit of the plasma membrane KATP-channel and that it also plays an unexpected but important role in the cAMP-dependent regulation of Ca2+-induced exocytosis.",
keywords = "Ca, CAMP, CAMP-GEFII, Insulin, SUR1",
author = "Lena Eliasson and Xiaosong Ma and Erik Renstr{\"o}m and Sebastian Barg and Berggren, {Per Olof} and Juris Galvanovskis and Jesper Gromada and Xingjun Jing and Ingmar Lundquist and Albert Salehi and Sabine Sewing and Patrik Rorsman",
year = "2003",
month = "3",
day = "1",
doi = "10.1085/jgp.20028707",
language = "English",
volume = "121",
pages = "181--197",
journal = "Journal of General Physiology",
issn = "0022-1295",
publisher = "Rockefeller University Press",
number = "3",

}

TY - JOUR

T1 - SUR1 regulates PKA-independent cAMP-induced granule priming in mouse pancreatic b-cells

AU - Eliasson, Lena

AU - Ma, Xiaosong

AU - Renström, Erik

AU - Barg, Sebastian

AU - Berggren, Per Olof

AU - Galvanovskis, Juris

AU - Gromada, Jesper

AU - Jing, Xingjun

AU - Lundquist, Ingmar

AU - Salehi, Albert

AU - Sewing, Sabine

AU - Rorsman, Patrik

PY - 2003/3/1

Y1 - 2003/3/1

N2 - Measurements of membrane capacitance were applied to dissect the cellular mechanisms underlying PKA-dependent and -independent stimulation of insulin secretion by cyclic AMP. Whereas the PKA-independent (Rp-cAMPS-insensitive) component correlated with a rapid increase in membrane capacitance of ∼80 fF that plateaued within ∼200 ms, the PKA-dependent component became prominent during depolarizations >450 ms. The PKA-dependent and -independent components of cAMP-stimulated exocytosis differed with regard to cAMP concentration dependence; the Kd values were 6 and 29 μM for the PKA-dependent and -independent mechanisms, respectively. The ability of cAMP to elicit exocytosis independently of PKA activation was mimicked by the selective cAMP-GEFII agonist 8CPT-2Me-cAMP. Moreover, treatment of B-cells with antisense oligodeoxynucleotides against cAMP-GEFII resulted in partial (50%) suppression of PKA-independent exocytosis. Surprisingly, B-cells in islets isolated from SUR1-deficient mice (SUR1-/- mice) lacked the PKA-independent component of exocytosis. Measurements of insulin release in response to GLP-1 stimulation in isolated islets from SUR1-/- mice confirmed the complete loss of the PKA-independent component. This was not attributable to a reduced capacity of GLP-1 to elevate intracellular cAMP but instead associated with the inability of cAMP to stimulate influx of Cl- into the granules, a step important for granule priming. We conclude that the role of SUR1 in the B cell extends beyond being a subunit of the plasma membrane KATP-channel and that it also plays an unexpected but important role in the cAMP-dependent regulation of Ca2+-induced exocytosis.

AB - Measurements of membrane capacitance were applied to dissect the cellular mechanisms underlying PKA-dependent and -independent stimulation of insulin secretion by cyclic AMP. Whereas the PKA-independent (Rp-cAMPS-insensitive) component correlated with a rapid increase in membrane capacitance of ∼80 fF that plateaued within ∼200 ms, the PKA-dependent component became prominent during depolarizations >450 ms. The PKA-dependent and -independent components of cAMP-stimulated exocytosis differed with regard to cAMP concentration dependence; the Kd values were 6 and 29 μM for the PKA-dependent and -independent mechanisms, respectively. The ability of cAMP to elicit exocytosis independently of PKA activation was mimicked by the selective cAMP-GEFII agonist 8CPT-2Me-cAMP. Moreover, treatment of B-cells with antisense oligodeoxynucleotides against cAMP-GEFII resulted in partial (50%) suppression of PKA-independent exocytosis. Surprisingly, B-cells in islets isolated from SUR1-deficient mice (SUR1-/- mice) lacked the PKA-independent component of exocytosis. Measurements of insulin release in response to GLP-1 stimulation in isolated islets from SUR1-/- mice confirmed the complete loss of the PKA-independent component. This was not attributable to a reduced capacity of GLP-1 to elevate intracellular cAMP but instead associated with the inability of cAMP to stimulate influx of Cl- into the granules, a step important for granule priming. We conclude that the role of SUR1 in the B cell extends beyond being a subunit of the plasma membrane KATP-channel and that it also plays an unexpected but important role in the cAMP-dependent regulation of Ca2+-induced exocytosis.

KW - Ca

KW - CAMP

KW - CAMP-GEFII

KW - Insulin

KW - SUR1

UR - http://www.scopus.com/inward/record.url?scp=0037337832&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0037337832&partnerID=8YFLogxK

U2 - 10.1085/jgp.20028707

DO - 10.1085/jgp.20028707

M3 - Article

C2 - 12601083

AN - SCOPUS:0037337832

VL - 121

SP - 181

EP - 197

JO - Journal of General Physiology

JF - Journal of General Physiology

SN - 0022-1295

IS - 3

ER -