Widespread synchronous [Ca2+]i oscillations due to bursting electrical activity in single pancreatic islets
Abstract
Pancreatic beta cells, tightly organized in the islet of Langerhans, secrete insulin in response to glucose in a calcium-dependent manner. The calcium input required for this secretory activity is thought to be provided by an oscillatory electrical activity occurring in the form of "bursts" of calcium action potentials. The previous observation that islet intracellular free Ca2+ levels undergo spontaneous oscillations in the presence of glucose, together with the fact that islet cells are coupled through gap junctions, hinted at a highly effective co-ordination between individual islet cells. Through the use of simultaneous recordings of intracellular calcium and membrane potential it is now reported that the islet calcium waves are synchronized with the beta cell bursting electrical activity. This observation suggests that each calcium wave is due to Ca2+ entering the cells during a depolarized phase of electrical activity. Moreover, fura-2 fluorescence image analysis indicates that calcium oscillations occur synchronously across the whole islet tissue. The maximal phase shift between oscillations occurring in different islet cells is estimated as 2 s. This highly co-ordinated oscillatory calcium signalling system may underlie pulsatile insulin secretion and the islet behaviour as a secretory "syncytium". Since increasing glucose concentration lengthens calcium wave and burst duration without significantly affecting wave amplitude, we further propose that it is the fractiona…
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β-cells are electrically coupled, and electrical activity and changes in [Ca2+]i spread across the islet synchronously with a wave initiated in one part and propagating to other parts with a slight delay.
“As β-cells are electrically coupled electrical activity and changes in [Ca2+]i spread across the islet in a synchronous fashion with the ‘wave’ being initiated in one part of the islet and then propagating to other parts with a slight delay(165, 440, 591).”
From Pancreatic β-Cell Electrical Activity and Insulin Secretion: Of Mice and Men (2018) · cites this paper as [591]
In mouse islets, glucose-induced [Ca2+]i oscillations tend to be synchronised across the entire islet.
“In mouse islets, glucose-induced [Ca2+]i oscillations tend to be synchronised across the entire islet (591), indicative of electrical coupling between β-cells.”
From Pancreatic β-Cell Electrical Activity and Insulin Secretion: Of Mice and Men (2018) · cites this paper as [591]
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“Additionally, most data about beta cell functional adaptation come from isolated beta cells [195,196], which are unable to fully capture the normal physiological scenario compared with isolated islets [197,198] or tissue slices [149,150].”
BackgroundOscillation of gap junction electrical coupling in the mouse pancreatic islets of Langerhans.
Andreu, E., Soria, B., & Sanchez-Andres, J. V. (1997) · The Journal of Physiology · doi:10.1113/jphysiol.1997.sp021899 · Cited by 58 · see citing works
Self-citationBeta-cell hubs maintain Ca2+ oscillations in human and mouse islet simulations
Lei, C. L., Kellard, J. A., Hara, M., Johnson, J. D., Rodríguez, B., & Briant, L. (2018) · Islets · doi:10.1080/19382014.2018.1493316 · Cited by 56 · see citing works
Enhanced Glucose Tolerance by SK4 Channel Inhibition in Pancreatic β-Cells
Düfer, M., Gier, B., Wolpers, D., Krippeit-Drews, P., Ruth, P., & Drews, G. (2009) · Diabetes · doi:10.2337/db08-1324 · Cited by 56 · see citing works
“Acute application of the SK4 channel blocker abrogated the oscillatory pattern of [Ca(2) ]c that characterizes glucose-stimulated -cells (39) and clearly augmented [Ca(2) ]c.”
BackgroundMathematical models of electrical activity of the pancreatic β-cell: A physiological review
Félix‐Martínez, G. J., & Godínez-Fernández, J. R. (2014) · Islets · doi:10.4161/19382014.2014.949195 · Cited by 63 · see citing works
“One important drawback of this model is that, as in other models described above, the slow dynamics of [Ca2C]i contradicts the fast dynamics observed experimentally.(29,30) However, Keizer and Magnus provided an equation for the KATP current that is still used in recent models.”
MethodResultRole of estrogen receptors alpha, beta and GPER1/GPR30 in pancreatic beta-cells
Nadal, Á. (2010) · Frontiers in bioscience · doi:10.2741/3686 · Cited by 54 · see citing works
Self-citationQuesada, I., Fuentes, E., Andreu, E., Meda, P., Nadal, A., & Soria, B. (2003) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.00473.2002 · Cited by 44 · see citing works
“Our results suggest that electrical coupling, which is a widespread event in the islet of Langerhans (2, 10, 12, 31, 39), might have a major role in islet synchronization rather than metabolic communication.”
BackgroundResultInfluentialSelf-citationArredouani, A., Henquin, J. C., & Gilon, P. (2002) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.00347.2001 · Cited by 50 · see citing works
“, prevents [Ca2 ]c from intermittently returning to basal levels) (14, 38).”
Smolen, P. D., & Keizer, J. (1992) · The Journal of Membrane Biology · doi:10.1007/bf00232754 · Cited by 73 · see citing works
“Cytosolic Ca 2+ is not required to change slowly in either of our wholecell models, and its time course appears rather similar to that observed in perfused islets (Santos et al., 1991).”
Crutzen, R., Virreira, M., Markadieu, N., Shlyonsky, V., Sener, A., Malaisse, W., Beauwens, R., Boom, A., & Golstein, P. (2015) · Pflügers Archiv: European Journal of Physiology · doi:10.1007/s00424-015-1758-5 · Cited by 52 · see citing works
“Variations in membrane potential are instrumental in inducing Ca variations [5, 59, 61], hence insulin release.”
BackgroundZhang, M., Fendler, B., Peercy, B., Goel, P., Bertram, R., Sherman, A., & Satin, L. (2008) · Biophysical Journal · doi:10.1529/biophysj.107.125088 · Cited by 52 · see citing works
Gilon, P., Jonas, J., & Henquin, J. (1994) · Diabetologia · doi:10.1007/bf00400464 · Cited by 52 · see citing works
“It has previously been established that, although islets from normal mice contain about 20 % of non-beta cells, the characteristics of the Ca# + signals recorded from the microorgan essentially reflect events occurring in beta cells [21, 22, 24, 26].”
InfluentialBergsten, P. (2002) · Diabetes · doi:10.2337/diabetes.51.2007.s171 · Cited by 50 · see citing works
“The in vitro results with progression from rapid oscillations in [Ca(2) ]i in freshly isolated islets (23,24,28) and islets with enhanced cAMP content (15,29) via islets showing a mixture of rapid and slow oscillations in [Ca(2) ]i (15,23,26,27,29,31) to islets with only slow oscillations in [Ca(2) ]i after extended c…”
BackgroundCritical and Supercritical Spatiotemporal Calcium Dynamics in Beta Cells
Gosak, M., Stožer, A., Markovič, R., Dolenšek, J., Perc, M., Rupnik, M., & Marhl, M. (2017) · Frontiers in Physiology · doi:10.3389/fphys.2017.01106 · Cited by 49 · see citing works
“…with synchronous membrane potential and [Ca2+]c oscillations that increase in plateau fraction with increasing glucose concentrations (Henquin et al., 1982; Henquin, 1987; Valdeolmillos et al., 1989; Santos et al., 1991; Gilon and Henquin, 1995; Jonkers et al., 1999; Jonkers and Henquin, 2001).”
BackgroundA fluorimetric and amperometric study of calcium and secretion in isolated mouse pancreatic ?-cells
Smith, P. A., Duchen, M. R., & Ashcroft, F. M. (1995) · Pfl�gers Archiv European Journal of Physiology · doi:10.1007/bf00386180 · Cited by 80 · see citing works
“There is a good correlation between /?-cell electrical activity and changes in [Ca2+]i when measured simultaneously from a single islet [ 33 , 40].”
MethodMartínez‐Pinna, J., Marroquí, L., Hmadcha, A., López‐Beas, J., Soriano, S., Villar-Pazos, S., Alonso‐Magdalena, P., dos Santos, R. S., Quesada, I., Martı́n, F., et al. (2019) · Diabetologia · doi:10.1007/s00125-019-4925-y · Cited by 58 · see citing works
Self-citationImpaired glucagon secretory responses in mice lacking the type 1 sulfonylurea receptor
Shiota, C., Rocheleau, J. V., Shiota, M., Piston, D. W., & Magnuson, M. A. (2005) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.00102.2005 · Cited by 44 · see citing works
“Although pancreatic -cells are electrically coupled with each other through gap junctions and exhibit synchronized [Ca(2) ]i oscillations (34), there is little evidence to date for direct electrical coupling between - and -cells (13, 28).”
BackgroundStožer, A., Klemen, M., Gosak, M., Bombek, L. K., Pohorec, V., Rupnik, M., & Dolenšek, J. (2020) · bioRxiv · doi:10.1101/2020.03.11.986893 · Cited by 44
Endogenous Fatty Acids Are Essential Signaling Factors of Pancreatic β-Cells and Insulin Secretion
Hauke, S., Keutler, K., Phapale, P. B., Yushchenko, D. A., & Schultz, C. (2018) · Diabetes · doi:10.2337/db17-1215 · Cited by 50 · see citing works
“Coupling of the secretory activity of pancreatic islets results in oscillatory elevations of insulin levels in the bloodstream (1).”
BackgroundEndocrine cells and blood vessels work in tandem to generate hormone pulses.
Schaeffer, M., Hodson, D., Lafont, C., & Mollard, P. (2011) · Journal of Molecular Endocrinology · doi:10.1530/jme-11-0035 · Cited by 43 · see citing works
A Model of Action Potentials and Fast Ca2+ Dynamics in Pancreatic β-Cells
Fridlyand, L. E., Jacobson, D. A., Kuznetsov, A., & Philipson, L. H. (2009) · Biophysical Journal · doi:10.1016/j.bpj.2009.01.029 · Cited by 37 · see citing works
Dahlgren, G. M., Kauri, L., & Kennedy, R. (2005) · Biochimica et Biophysica Acta · doi:10.1016/j.bbagen.2005.04.007 · Cited by 42 · see citing works
Herrington, J. B., Sánchez, M., Wunderler, D., Yan, L., Bugianesi, R. M., Dick, I. E., Clark, S. A., Brochu, R. M., Priest, B. T., Köhler, M. G., et al. (2005) · The Journal of Physiology · doi:10.1113/jphysiol.2005.089375 · Cited by 42 · see citing works
- Authors
- Santos, R. M., Rosario, L. M., Nadal, A., Garcia-Sancho, J., Soria, B., & Valdeolmillos, M.
- Affiliations
- University of Alicante (ES)
- Venue
- Pfl�gers Archiv European Journal of Physiology
- Published
- 1991-05
- Volume
- 418
- Issue
- 4
- Pages
- 417-422
- ISSN
- 0031-6768 (ISSN-L)
- 1432-2013
- OpenAlex
- W1973533455
- Cited by
- 350
- References
- 0
- Citations by year
- 2026: 1 · 2025: 2 · 2024: 4 · 2023: 6 · 2022: 5 · 2021: 11 · 2020: 3 · 2019: 5 · 2018: 5 · 2017: 10 · 2016: 6 · 2015: 8 · 2014: 10 · 2013: 13 · 2012: 8
- FWCI
- 19.18
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Pflügers Archiv - European Journal of Physiology (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Health Sciences › Medicine › Surgery › Pancreatic function and diabetes
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Connexins and lens biology
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ion channel regulation and function
- Keywords
- calcium oscillations, pancreatic beta cells, pancreatic islets, calcium waves, calcium action potentials, electrical coupling, insulin secretion, glucose stimulation, syncytium, calcium signaling, membrane potential, Fura-2 imaging
- MeSH terms
- Action Potentials, Animals, Calcium, Electric Conductivity, Glucose, Image Processing, Computer-Assisted, Insulin, Intracellular Fluid, Islets of Langerhans, Membrane Potentials, Fura-2, Mice
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