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Cited by 60Pancreatic function and diabetesAdenosine and Purinergic SignalingCalcium signaling and nucleotide metabolism

Vesicular nucleotide transporter-mediated ATP release regulates insulin secretion.

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Geisler, Jessica C., Corbin, Kathryn L., Li, Qin, Feranchak, Andrew P., Nunemaker, Craig S., Li, Chien·2013·Endocrinology
DOI 10.1210/en.2012-1818PMC PMC3548185
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Abstract

Extracellular ATP plays a critical role in regulating insulin secretion in pancreatic β cells. The ATP released from insulin secretory vesicles has been proposed to be a major source of extracellular ATP. Currently, the mechanism by which ATP accumulates into insulin secretory granules remains elusive. In this study, the authors identified the expression of a vesicular nucleotide transporter (VNUT) in mouse pancreas, isolated mouse islets, and MIN6 cells, a mouse β cell line. Immunohistochemistry and immunofluorescence revealed that VNUT colocalized extensively with insulin secretory granules. Functional studies showed that suppressing endogenous VNUT expression in β cells by small hairpin RNA knockdown greatly reduced basal- and glucose-induced ATP release. Importantly, knocking down VNUT expression by VNUT small hairpin RNA in MIN6 cells and isolated mouse islets dramatically suppressed basal insulin release and glucose-stimulated insulin secretion (GSIS). Moreover, acute pharmacologic blockade of VNUT with Evans blue, a VNUT antagonist, greatly attenuated GSIS in a dose-dependent manner. Exogenous ATP treatment effectively reversed the insulin secretion defect induced by both VNUT knockdown and functional inhibition, indicating that VNUT-mediated ATP release is essential for maintaining normal insulin secretion. In contrast to VNUT knockdown, overexpression of VNUT in β cells resulted in excessive ATP release and enhanced basal insulin secretion and GSIS. Elevated insulin secretion induced by VNUT overexpression was reversed by pharmacologic inhibition of P2X but not P2Y purinergic receptors. This study reveals VNUT is expressed in pancreatic β cells and plays an essential and novel role in regulating insulin secretion through vesicular ATP release and extracellular purinergic signaling.

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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 [202]

    The section ‘VNUT overexpression enhances insulin secretion by activating P2X purinergic receptors’ reports that blocking P2X receptors significantly reduced glucose-stimulated insulin secretion in control mouse islets. The paper does not report the same receptor-blockade result in human β-cells; its Discussion mentions human islets only in connection with insulin secretion stimulated by added ATP. Page numbers are unavailable in our copy. (LLM, conf=0.86)

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Cited by

Sorted by citations

Authors
Geisler, J. C., Corbin, K. L., Li, Q., Feranchak, A. P., Nunemaker, C. S., & Li, C.
Affiliations
  • University of Virginia Health System (US)
  • University of Virginia (US)
  • The University of Texas Southwestern Medical Center (US)
Corresponding author
Li, Chien
ORCID
Venue
Endocrinology
Publisher
The Endocrine Society
Published
2012-12-19
Volume
154
Issue
2
Pages
675-684
ISSN
  • 0013-7227 (ISSN-L)
  • 1945-7170
DOI
10.1210/en.2012-1818
PMC
PMC3548185
OpenAlex
W2137750454
Cited by
60
References
1
Citations by year
2026: 4 · 2025: 1 · 2024: 1 · 2023: 2 · 2022: 5 · 2021: 6 · 2020: 4 · 2019: 5 · 2018: 5 · 2017: 7 · 2016: 1 · 2015: 5 · 2014: 10 · 2013: 4
FWCI
6.19
Type
journal article
Language
en
Open access
Locations
  • Endocrinology (publishedVersion)
  • Europe PMC (PubMed Central) (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
Funders
  • National Institute of General Medical Sciences (T32GM007055)
  • National Institute of Diabetes and Digestive and Kidney Diseases (R01DK078587, R01DK078049, DK-078587, R01DK089182)
Topics
  • Health Sciences › Medicine › Surgery › Pancreatic function and diabetes
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Physiology › Adenosine and Purinergic Signaling
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Physiology › Calcium signaling and nucleotide metabolism
Keywords
vesicular nucleotide transporter, ATP release, insulin secretion, pancreatic beta cells, insulin secretory granules, glucose-stimulated insulin secretion, purinergic signaling, P2X receptors, P2Y receptors, extracellular ATP, MIN6 cells, islets
MeSH terms
Insulin Secretion, Adenosine Triphosphate, Animals, Cell Line, Evans Blue, Glucose, Insulin, Male, Secretory Vesicles, Nucleotide Transport Proteins, Insulin-Secreting Cells, Mice, Gene Knockdown Techniques

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