Protein kinase A‐dependent and ‐independent stimulation of exocytosis by cAMP in mouse pancreatic B‐cells
Open accessAbstract
The mechanisms by which cAMP stimulates Ca 2+ ‐dependent insulin secretion were investigated by combining measurements of whole‐cell Ca 2+ currents, the cytoplasmic free Ca 2+ concentration ([Ca 2+ ] i ) and membrane capacitance in single mouse B‐cells maintained in tissue culture. Cyclic AMP stimulated exocytosis > 4‐fold in whole‐cell experiments in which secretion was evoked by intracellular dialysis with a Ca 2+ ‐EGTA buffer with a [Ca 2+ ] i of 1.5μ m . This effect was antagonized by inhibitors of protein kinase A (PKA). Photorelease of cAMP from a caged precursor potentiated exocytosis at Ca 2+ concentrations which were themselves stimulatory (≥60 n m ), but was without effect in the complete absence of Ca 2+ . Elevation of intracellular cAMP (by exposure to forskolin) evoked a 6‐fold PKA‐dependent enhancement of the maximal exocytotic response (determined as the maximum increase in cell capacitance that could be elicited by a train of depolarizations) in perforated‐patch whole‐cell recordings. Exocytosis triggered by single depolarizations in standard whole‐cell recordings was strongly potentiated by cAMP, but in this case the effect was unaffected by PKA inhibition. When exocytosis was triggered by Ca 2+ released from Ca 2+ ‐NP‐EGTA (‘caged Ca 2+ ), cAMP exerted a dual stimulatory effect on secretion: a rapid (initiated within 80 ms) PKA‐ independent phase and a late PKA‐dependent component. We conclude that cAMP stimulates insulin secretion both by increasing the release probability of secretory granules already in the readily releasable pool and by accelerating the refilling of this pool.
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When β-cells were exposed to forskolin or to ACh, the RRP increased 3- to 4-fold relative to that seen under control conditions.
“When β-cells were exposed to forskolin (to increase cAMP and activate both PKA and Epac2) or to ACh (to mobilize intracellular Ca2+ and activate CAMKII), the RRP increased 3- to 4-fold relative that seen under control conditions (241, 545).”
From Pancreatic β-Cell Electrical Activity and Insulin Secretion: Of Mice and Men (2018) · cites this paper as [545]
The paper’s numbered findings report that forskolin produced a sixfold increase in the maximal exocytotic response, not a three- to fourfold increase in readily releasable pool (RRP) size. Its conclusion discusses increased release probability and faster RRP refilling; the passages in our copy do not report an ACh treatment or the claimed RRP-size comparison. (LLM, conf=0.83)
Experimental — accuracy not yet measuredGranule mobilization is accelerated by cAMP via activation of PKA.
“Granule mobilization is accelerated by cAMP (via activation of PKA) (545) and by Ca2+ (via activation of CAMKII) (241).”
From Pancreatic β-Cell Electrical Activity and Insulin Secretion: Of Mice and Men (2018) · cites this paper as [545]
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- Authors
- Renström, E., Eliasson, L., & Rorsman, P.
- Affiliations
- Novo Nordisk (Denmark) (DK)
- University of Gothenburg (SE)
- Corresponding author
- Renström, E.
- Venue
- The Journal of Physiology
- Publisher
- Wiley
- Published
- 1997-07
- Volume
- 502
- Issue
- 1
- Pages
- 105-118
- ISSN
- 0022-3751 (ISSN-L)
- 1469-7793
- PMC
- PMC1159575
- OpenAlex
- W1988196562
- Cited by
- 299
- References
- 0
- Citations by year
- 2026: 2 · 2025: 2 · 2024: 4 · 2023: 2 · 2022: 5 · 2021: 6 · 2020: 5 · 2019: 6 · 2018: 5 · 2017: 11 · 2016: 6 · 2015: 11 · 2014: 13 · 2013: 7 · 2012: 22
- FWCI
- 12.68
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- The Journal of Physiology (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Lund University Publications (Lund University) (submittedVersion)
- 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
- cyclic AMP, protein kinase A, exocytosis, insulin secretion, pancreatic beta cells, calcium-dependent secretion, readily releasable pool, secretory granules, release probability, forskolin, intracellular calcium, membrane capacitance
- MeSH terms
- Cyclic AMP, Animals, Calcium, Cells, Cultured, Cytoplasmic Granules, Enzyme Inhibitors, Exocytosis, Colforsin, Islets of Langerhans, Mice, Inbred Strains, Photochemistry, Thionucleotides, Cyclic AMP-Dependent Protein Kinases, Patch-Clamp Techniques, Mice
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