A Subset of 50 Secretory Granules in Close Contact With l-Type Ca2+ Channels Accounts for First-Phase Insulin Secretion in Mouse β-Cells
Abstract
Capacitance measurements were applied to mouse pancreatic beta-cells to elucidate the cellular mechanisms underlying biphasic insulin secretion. We report here that only 10,000 granules are immediately available for release. The releasable granules tightly associate with the voltage-gated alpha(1C) Ca(2+) channels, and it is proposed that the release of these granules accounts for first-phase insulin secretion. Subsequent replenishment of the releasable pool by priming of previously nonreleasable granules is required for second-phase insulin secretion. The latter reaction depends on intragranular acidification due to the concerted action of granular bafilomycin-sensitive v-type H(+)-ATPase and 4,4-diisothiocyanostilbene-2,2-disulfonate--blockable ClC-3 Cl(-) channels. Lowering the cytoplasmic ATP/ADP ratio prevents granule acidification, granule priming, and refilling of the releasable pool. The latter finding provides an explanation to the transient nature of insulin secretion elicited by, for example, high extracellular K(+) in the absence of metabolizable fuels.
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At ADP concentrations >1 mM, depolarization-evoked exocytosis in the presence of 3 mM ATP was reduced by 80%.
“At ADP concentrations >1 mM, depolarization-evoked exocytosis in the presence of 3 mM ATP was reduced by 80%.”
From Pancreatic β-Cell Electrical Activity and Insulin Secretion: Of Mice and Men (2018) · cites this paper as [45]
Exocytosis is reduced by increasing concentrations of ADP with an IC50 of ~0.3 mM.
“However, exocytosis is reduced by increasing concentrations of ADP with an IC50 of ~0.3 mM.”
From Pancreatic β-Cell Electrical Activity and Insulin Secretion: Of Mice and Men (2018) · cites this paper as [45]
ADP does not affect the release of RRP granules but interferes with granule mobilization/priming.
“ADP does not affect the release of RRP granules but interferes with granule mobilization/priming (45).”
From Pancreatic β-Cell Electrical Activity and Insulin Secretion: Of Mice and Men (2018) · cites this paper as [45]
This Ca2+ channel density is only 5-10% of that found in adrenal chromaffin cells, where the Ca2+ channel density is as high as 20 channels/μm2.
“This is only 5-10% of that found in adrenal chromaffin cells, where the Ca2+ channel density is as high as 20 channels/μm2 (45).”
From Pancreatic β-Cell Electrical Activity and Insulin Secretion: Of Mice and Men (2018) · cites this paper as [45]
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“In pancreatic β-cells, a similar strong dependence of exocytosis on Ca2+ entry through L-type Ca2+ channels has been attributed to a physical interaction between the tail of the L-type Ca2+ channel and the exocytotic vesicles (Barg et al. 2002).”
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“The first and second phases are associated with exocytosis of insulin granules from the RRP and a reserve pool (RP), respectively (Henquin, 2000; Barg et al., 2002; Bratanova-Tochkova et al., 2002).”
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“%) exist in a functionally defined readily releasable pool (RRP) (Barg et al., 2002).”
BackgroundMunc18c Depletion Selectively Impairs the Sustained Phase of Insulin Release
Oh, E., & Thurmond, D. C. (2009) · Diabetes · doi:10.2337/db08-1059 · Cited by 64 · see citing works
“Granules located in the 50-nm group have been termed “morphologically docked” in the literature (18).”
BackgroundInfluentialExocytotic Properties of Human Pancreatic β‐cells
Braun, M., Ramracheya, R., Johnson, P. R., & Rorsman, P. (2009) · Annals of the New York Academy of Sciences · doi:10.1111/j.1749-6632.2008.03992.x · Cited by 60 · see citing works
Self-citationAction potentials and insulin secretion: new insights into the role of Kv channels
Jacobson, D. A., & Philipson, L. H. (2007) · Diabetes, obesity and metabolism · doi:10.1111/j.1463-1326.2007.00784.x · Cited by 55 · see citing works
Uenishi, E., Shibasaki, T., Takahashi, H., Seki, C., Hamaguchi, H., Yasuda, T., Tatebe, M., Oiso, Y., Takenawa, T., & Seino, S. (2013) · Journal of Biological Chemistry · doi:10.1074/jbc.m113.464420 · Cited by 54 · see citing works
“It is generally thought that pancreatic -cells contain at least two pools of insulin secretory granules that differ in release competence as follows: a reserve pool (RP) that accounts for most of the granules, and a readily releasable pool (RRP) that accounts for the other 5% (9, 10).”
BackgroundKinetics of Rab27a‐dependent actions on vesicle docking and priming in pancreatic β‐cells
Merrins, M. J., & Stuenkel, E. L. (2008) · The Journal of Physiology · doi:10.1113/jphysiol.2008.158477 · Cited by 51 · see citing works
“…for first-phase insulin secretion (via KATP channel-dependent pathways), while the sustained second-phase release requires their refilling from a reserve pool (involving KATP channel-independent pathways) (Eliasson et al. 1996; Barg et al. 2001, 2002; Olofsson et al. 2002; Straub & Sharp, 2002).”
BackgroundThe Prohormone VGF Regulates β Cell Function via Insulin Secretory Granule Biogenesis
Stephens, S. B., Edwards, R. J., Sadahiro, M., Lin, W., Jiang, C. S., Salton, S. R., & Newgard, C. B. (2017) · Cell Reports · doi:10.1016/j.celrep.2017.08.050 · Cited by 66 · see citing works
Insulin granule trafficking in β-cells: mathematical model of glucose-induced insulin secretion
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“According to a well-established view (2, 48), within the pool of docked and primed granules here denoted by D, a pool of immediately releasable granules, DIR, must be distinguished.”
BackgroundInfluentialRecent Insights into Beta-cell Exocytosis in Type 2 Diabetes
Thurmond, D. C., & Gaisano, H. Y. (2019) · Journal of Molecular Biology · doi:10.1016/j.jmb.2019.12.012 · Cited by 53 · see citing works
Plasma membrane depolarization as a determinant of the first phase of insulin secretion
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“This response is often regarded as being equivalent to the first phase of glucoseinduced insulin secretion (31), which conforms with the view that the first phase is due to a limited pool of secretion-ready granules requiring only one final signal that is provided by the [Ca(2) ]i elevation in the vicinity of voltage-…”
BackgroundRevisiting the role of SNAREs in exocytosis and membrane fusion
Szule, J. A., & Coorssen, J. R. (2003) · Biochimica et Biophysica Acta (BBA) - Molecular Cell Research · doi:10.1016/s0167-4889(03)00095-8 · Cited by 50 · see citing works
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Insulin secretion and insulin-producing tumors
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The RalA GTPase Is a Central Regulator of Insulin Exocytosis from Pancreatic Islet Beta Cells
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“This rate is similar to what has been measured in pancreatic β-cells using the same intracellular solution (Proks et al. 1996; Barg et al. 2002; Olofsson et al. 2009).”
BackgroundResultEpidermal growth factor increases insulin secretion and lowers blood glucose in diabetic mice
Lee, H., Yea, K., Kim, J. H., Lee, B., Chae, Y., Kim, H., Lee, D. W., Kim, S. H., Cho, J., Jin, C.-J., et al. (2007) · Journal of Cellular and Molecular Medicine · doi:10.1111/j.1582-4934.2007.00169.x · Cited by 48
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“A subset of RRP vesicles appear tightly associated with the L-type voltagedependent Ca2+-channels and their fusion with the plasma membrane gives rise to a very fast component of exocytosis (immediately releasable pool, IRP; Barg et al. 2001, 2002).”
BackgroundSelf-citationMonitoring C-Peptide Storage and Secretion in Islet β-Cells In Vitro and In Vivo
Zhu, S., Larkin, D. D., Lu, S., Inouye, C. M., Haataja, L., Anjum, A., Kennedy, R., Castle, D. J., & Arvan, P. R. (2015) · Diabetes · doi:10.2337/db15-1264 · Cited by 43 · see citing works
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Glucose-dependent docking and SNARE protein-mediated exocytosis in mouse pancreatic alpha-cell
Andersson, S. A., Pedersen, M. G., Vikman, J., & Eliasson, L. (2011) · Pflügers Archiv - European Journal of Physiology · doi:10.1007/s00424-011-0979-5 · Cited by 46 · see citing works
“A smaller fraction of the granules are suggested to be primed and belong to a readily releasable pool of granules (RRP) situated at the release site, in similarity to the situation in pancreatic beta-cells [1] and other neuroendocrine cells [23].”
Self-citationVikman, J., Svensson, H., Huang, Y., Kang, Y., Andersson, S. A., Gaisano, H. Y., & Eliasson, L. (2009) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.90585.2008 · Cited by 44 · see citing works
Self-citationDynamin Is Functionally Coupled to Insulin Granule Exocytosis
Min, L., Leung, Y., Tomás, A., Watson, R. T., Gaisano, H. Y., Halban, P. A., Pessin, J. E., & Hou, J. C. (2007) · Journal of Biological Chemistry · doi:10.1074/jbc.m703402200 · Cited by 42 · see citing works
The role of adherens junction proteins in the regulation of insulin secretion
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“Al- though the mechanisms of acidification remain uncertain, the idea that pH changes may facilitate secretion by affecting exocytotic proteins, making them more fusogenic, has also been considered (Barg et al., 2001, 2002; Yang et al., 2002; Renstrom et al., 2002).”
BackgroundA fluorescent timer reporter enables sorting of insulin secretory granules by age
Yau, B., Hays, L. B., Liang, C., Laybutt, D. R., Thomas, H. E., Gunton, J. E., Williams, L. J., Hawthorne, W. J., Thorn, P., Rhodes, C. J., et al. (2020) · Journal of Biological Chemistry · doi:10.1074/jbc.ra120.012432 · Cited by 47 · see citing works
Modulation of Ionic Channels and Insulin Secretion by Drugs and Hormones in Pancreatic Beta Cells
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Signal integration at the level of ion channel and exocytotic function in pancreatic β-cells
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Pedersen, M. G., Tagliavini, A., & Henquin, J. (2019) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.00380.2018 · Cited by 43 · see citing works
“117 118 Studies of exocytosis in single β-cells provided substantial support to the 119 pool model, with depletion of a readily releasable pool (RRP) yielding the first 120 phase, while refilling of the RRP creating the second phase (2, 10, 48, 58).”
BackgroundA Spatial Model of Insulin‐Granule Dynamics in Pancreatic β‐Cells
Dehghany, J., Hoboth, P., Ivanova, A., Mziaut, H., Müller, A., Kalaidzidis, Y. L., Solimena, M., & Meyer‐Hermann, M. (2015) · Traffic · doi:10.1111/tra.12286 · Cited by 21 · see citing works
- Authors
- Barg, S., Eliasson, L., Renström, E., & Rorsman, P.
- Affiliations
- Lund University (SE)
- From the Department of Molecular and Cellular Physiology, Institute of Physiology, Lund University, Lund, Sweden
- Venue
- Diabetes
- Publisher
- American Diabetes Association
- Published
- 2002-02-01
- Volume
- 51
- Issue
- suppl_1
- Pages
- S74-S82
- ISSN
- 0012-1797 (ISSN-L)
- 1939-327X
- OpenAlex
- W2050076638
- Cited by
- 227
- References
- 0
- Citations by year
- 2026: 2 · 2025: 4 · 2024: 6 · 2023: 4 · 2022: 5 · 2021: 9 · 2020: 4 · 2019: 10 · 2018: 5 · 2017: 7 · 2016: 7 · 2015: 14 · 2014: 6 · 2013: 8 · 2012: 14
- FWCI
- 3.18
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Diabetes (publishedVersion)
- PubMed (publishedVersion)
- Lund University Publications (Lund University) (submittedVersion)
- Funders
- Vetenskapsrådet
- 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
- insulin secretion, secretory granules, L-type calcium channels, first-phase insulin secretion, second-phase insulin secretion, pancreatic beta cells, V-ATPase, ClC-3 chloride channel, ATP/ADP ratio
- MeSH terms
- Insulin Secretion, Animals, Insulin, Islets of Langerhans, Calcium Channels, L-Type, Secretory Vesicles, Mice
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