SUR1 Regulates PKA-independent cAMP-induced Granule Priming in Mouse Pancreatic B-cells
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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.
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Many potentiators of insulin secretion exert a direct effect on late steps of exocytosis in addition to stimulating β-cell electrical activity.
“Many potentiators of insulin secretion exert a direct effect on late steps of exocytosis in addition to stimulating β-cell electrical activity.”
From Pancreatic β-Cell Electrical Activity and Insulin Secretion: Of Mice and Men (2018) · cites this paper as [170]
GLP-1 stimulates exocytosis via Epac2.
“For example, GLP-1 stimulates exocytosis via Epac2 (170) and by cAMP-dependent activation of PKA, which phosphorylates synaptotagmin-7 at serine-103 (735).”
From Pancreatic β-Cell Electrical Activity and Insulin Secretion: Of Mice and Men (2018) · cites this paper as [170]
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Barg, S., Eliasson, L., Renström, E., & Rorsman, P. (2002) · Diabetes · doi:10.2337/diabetes.51.2007.s74 · Cited by 227 · cited 1× · see citing works
“The importance of the metabolic state for exocytosis is witnessed by the prompt (within a few seconds) inhibition when the cytoplasmic ATP/ADP-ratio is lowered by flash photolysis of caged ADP even if ATP and Ca 2 (cid:5) are present at levels that would otherwise be stimulatory (Barg et al., 2002a).”
Self-citationPriming of insulin granules for exocytosis by granular Cl(-) uptake and acidification
Barg, S., Huang, P., Eliasson, L., Nelson, D. J., Obermüller, S., Rorsman, P., Thévenod, F., & Renström, E. (2001) · Journal of Cell Science · doi:10.1242/jcs.114.11.2145 · Cited by 194 · see citing works
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- Authors
- Eliasson, L., Ma, X., Renström, E., Barg, S., Berggren, P.-O., Galvanovskis, J., Gromada, J., Jing, X., Lundquist, I., Salehi, A., Sewing, S., & Rorsman, P.
- Affiliations
- Lund University (SE)
- 1Department of Molecular and Cellular Physiology, Institute of Physiological Sciences, SE-221 84 Lund, Sweden
- Karolinska Institutet (SE)
- 3Lilly Research Laboratories, D-22419 Hamburg, Germany
- Corresponding author
- Rorsman, Patrik
- ORCID
- Venue
- The Journal of General Physiology
- Publisher
- Rockefeller University Press
- Published
- 2003-02-24
- Volume
- 121
- Issue
- 3
- Pages
- 181-197
- ISSN
- 0022-1295 (ISSN-L)
- 1540-7748
- PMC
- PMC2217330
- OpenAlex
- W2164561590
- Cited by
- 257
- References
- 3
- Citations by year
- 2026: 2 · 2025: 3 · 2024: 3 · 2023: 3 · 2022: 4 · 2021: 6 · 2020: 1 · 2019: 4 · 2018: 5 · 2017: 9 · 2016: 4 · 2015: 17 · 2014: 19 · 2013: 12 · 2012: 25
- FWCI
- 17.72
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- The Journal of General Physiology (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion, cc-by-nc-sa)
- PubMed Central (publishedVersion, cc-by-nc-sa)
- PubMed (publishedVersion)
- Lund University Publications (Lund University) (submittedVersion, other-oa)
- Funders
- National Institute of Diabetes and Digestive and Kidney Diseases (DK 58508, R01DK058508)
- Topics
- Health Sciences › Medicine › Surgery › Pancreatic function and diabetes
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Cellular transport and secretion
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Physiology › Calcium signaling and nucleotide metabolism
- Keywords
- SUR1, pancreatic beta cells, cAMP signaling, insulin secretion, membrane capacitance, glucagon-like peptide-1, chloride uptake
- MeSH terms
- Insulin Secretion, Cyclic AMP, Animals, Cells, Cultured, Electrophysiology, Exocytosis, Glucagon, Glucose, Insulin, Islets of Langerhans, Mice, Inbred Strains, Peptide Fragments, Protein Precursors, Receptors, Drug, Time Factors, Potassium Channels, Cyclic AMP-Dependent Protein Kinases, Mice, Knockout, ATP-Binding Cassette Transporters, Guanine Nucleotide Exchange Factors, Secretory Vesicles, Potassium Channels, Inwardly Rectifying, Electric Capacitance, Mice, Glucagon-Like Peptide 1, Sulfonylurea Receptors
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