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SUR1 Regulates PKA-independent cAMP-induced Granule Priming in Mouse Pancreatic B-cells.

Eliasson, Lena LU ; Ma, Xiaosong LU ; Renström, Erik LU ; Barg, Sebastian; Berggren, Per-Olof; Galvanovskis, Juris LU ; Gromada, Jesper; Jing, Xingjun; Lundquist, Ingmar LU and Salehi, Albert, et al. (2003) In Journal of General Physiology 121(3). p.181-197
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... (More)
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. (Less)
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Journal of General Physiology
volume
121
issue
3
pages
181 - 197
publisher
Rockefeller Institute for Medical Research
external identifiers
  • wos:000181447800001
  • scopus:0037337832
ISSN
0022-1295
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language
English
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yes
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bd4ef887-74c0-442d-9da4-ae5e4c2d89a7 (old id 112227)
date added to LUP
2007-07-11 16:09:48
date last changed
2018-05-29 12:04:40
@article{bd4ef887-74c0-442d-9da4-ae5e4c2d89a7,
  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.},
  author       = {Eliasson, Lena and Ma, Xiaosong and Renström, Erik and Barg, Sebastian and Berggren, Per-Olof and Galvanovskis, Juris and Gromada, Jesper and Jing, Xingjun and Lundquist, Ingmar and Salehi, Albert and Sewing, Sabine and Rorsman, Patrik},
  issn         = {0022-1295},
  language     = {eng},
  number       = {3},
  pages        = {181--197},
  publisher    = {Rockefeller Institute for Medical Research},
  series       = {Journal of General Physiology},
  title        = {SUR1 Regulates PKA-independent cAMP-induced Granule Priming in Mouse Pancreatic B-cells.},
  url          = {http://dx.doi.org/},
  volume       = {121},
  year         = {2003},
}