ATP-gated P2X 3 receptors constitute a positive autocrine signal for insulin release in the human pancreatic β cell
Open accessAbstract
Extracellular ATP has been proposed as a paracrine signal in rodent islets, but it is unclear what role ATP plays in human islets. We now show the presence of an ATP signaling pathway that enhances the human β cell's sensitivity and responsiveness to glucose fluctuations. By using in situ hybridization, RT-PCR, immunohistochemistry, and Western blotting as well as recordings of cytoplasmic-free Ca 2+ concentration, [Ca 2+ ] i , and hormone release in vitro, we show that human β cells express ionotropic ATP receptors of the P2X 3 type and that activation of these receptors by ATP coreleased with insulin amplifies glucose-induced insulin secretion. Released ATP activates P2X 3 receptors in the β-cell plasma membrane, resulting in increased [Ca 2+ ] i and enhanced insulin secretion. Therefore, in human islets, released ATP forms a positive autocrine feedback loop that sensitizes the β cell's secretory machinery. This may explain how the human pancreatic β cell can respond so effectively to relatively modest changes in glucose concentration under physiological conditions in vivo.
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GIIS is reduced in both human and mouse β-cells when purinergic receptor activation is prevented.
“Indeed, GIIS is reduced in both human and mouse β-cells when purinergic receptor activation is prevented (202, 312, 347, 737).”
From Pancreatic β-Cell Electrical Activity and Insulin Secretion: Of Mice and Men (2018) · cites this paper as [312]
The Results (pp. 2–3) show that blocking certain P2 receptors reduced glucose-induced insulin secretion in human islets. The paper does not show the same effect in mouse β-cells; its Discussion (p. 5) instead emphasizes species differences and says ATP did not evoke insulin responses in mouse islets at low glucose. (LLM, conf=0.90)
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Cites
Brissova, M., Fowler, M. J., Nicholson, W. E., Chu, A., Hirshberg, B., Harlan, D. M., & Powers, A. C. (2005) · Journal of Histochemistry & Cytochemistry · doi:10.1369/jhc.5c6684.2005 · Cited by 797 · see citing works
Braun, M., Ramracheya, R., Bengtsson, M., Zhang, Q., Karanauskaite, J., Partridge, C., Johnson, P. R., & Rorsman, P. (2008) · Diabetes · doi:10.2337/db07-0991 · Cited by 417 · cited 1× · see citing works
“That ATP failed to increase insulin secretion in the presence of Cd or nifedipine indicates that P2X receptor activation caused sufficient depolarization to activate voltage-dependent Ca channels (15, 17, 47), particularly L-type Ca channels critical to action potential firing in human β cells (48).”
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- [1]Conn PM, Goodman HM, Kostyo JL (1998) The Endocrine System (Oxford University Press, New York), pp 1 -5.
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Pancreatic β-Cell Electrical Activity and Insulin Secretion: Of Mice and Men
Rorsman, P., & Ashcroft, F. M. (2018) · Physiological Reviews · doi:10.1152/physrev.00008.2017 · Cited by 793 · see citing works
Astrocyte-derived ATP modulates depressive-like behaviors
Cao, X., Li, L.-P., Wang, Q., Wu, Q., Hu, H.-H., Zhang, M., Fang, Y.-Y., Zhang, J., Li, S.-J., Xiong, W.-C., et al. (2013) · Nature Medicine · doi:10.1038/nm.3162 · Cited by 615 · see citing works
Regulation of Insulin Secretion in Human Pancreatic Islets
Rorsman, P., & Braun, M. (2013) · Annual Review of Physiology · doi:10.1146/annurev-physiol-030212-183754 · Cited by 599 · see citing works
- Authors
- Jacques-Silva, M. C., Correa-Medina, M., Cabrera, O., Rodriguez-Diaz, R., Makeeva, N., Fachado, A., Diez, J., Berman, D. M., Kenyon, N. S., Ricordi, C., Pileggi, A., Molano, R. D., Berggren, P.-O., & Caicedo, A.
- Affiliations
- University of Miami (US)
- Diabetes Research Institute, Miller School of Medicine, University of Miami, Miami, FL 33136; and
- ORCID
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2010-03-22
- Volume
- 107
- Issue
- 14
- Pages
- 6465-6470
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC2851966
- OpenAlex
- W2006406278
- Cited by
- 127
- References
- 2
- Citations by year
- 2026: 3 · 2025: 5 · 2024: 5 · 2023: 4 · 2022: 9 · 2021: 7 · 2020: 10 · 2019: 7 · 2018: 4 · 2017: 6 · 2016: 7 · 2015: 6 · 2014: 9 · 2013: 20 · 2012: 14
- FWCI
- 9.13
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Howard Hughes Medical Institute
- Juvenile Diabetes Research Foundation International (4-2004-361)
- Diabetes Research Institute Foundation
- Novo Nordisk
- Vetenskapsrådet
- National Institutes of Health
- National Institute of Diabetes and Digestive and Kidney Diseases (R01DK055347, 1R01-DK55347-IU42RR016603, R03DK075487)
- National Center for Research Resources (M01RR016587, U42RR016603)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Physiology › Adenosine and Purinergic Signaling
- Health Sciences › Medicine › Surgery › Pancreatic function and diabetes
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Physiology › Calcium signaling and nucleotide metabolism
- Keywords
- P2X3 receptor, ATP signaling, insulin secretion, pancreatic beta cells, autocrine signaling, glucose-induced insulin release, intracellular calcium, human pancreatic islets
- MeSH terms
- Insulin Secretion, Adenosine Triphosphate, Calcium, Humans, Insulin, Signal Transduction, Receptors, Purinergic P2, Autocrine Communication, Insulin-Secreting Cells, Receptors, Purinergic P2X3
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