Purinergic Signalling

, 4:393 | Cite as

Extracellular ATP and zinc are co-secreted with insulin and activate multiple P2X purinergic receptor channels expressed by islet beta-cells to potentiate insulin secretion

  • Clintoria Richards-Williams
  • Juan L. Contreras
  • Kathleen H. Berecek
  • Erik M. SchwiebertEmail author
Original Article


It is well established that ATP is co-secreted with insulin and zinc from pancreatic beta-cells (β-cells) in response to elevations in extracellular glucose concentration. Despite this knowledge, the physiological roles of extracellular secreted ATP and zinc are ill-defined. We hypothesized that secreted ATP and zinc are autocrine purinergic signaling molecules that activate P2X purinergic receptor (P2XR) channels expressed by β-cells to enhance glucose-stimulated insulin secretion (GSIS). To test this postulate, we performed ELISA assays for secreted insulin at fixed time points within a “real-time” assay and confirmed that the physiological insulin secretagogue glucose stimulates secretion of ATP and zinc into the extracellular milieu along with insulin from primary rat islets. Exogenous ATP and zinc alone or together also induced insulin secretion in this model system. Most importantly, the presence of an extracellular ATP scavenger, a zinc chelator, and P2 receptor antagonists attenuated GSIS. Furthermore, mRNA and protein were expressed in immortalized β-cells and primary islets for a unique subset of P2XR channel subtypes, P2X2, P2X3, P2X4, and P2X6, which are each gated by extracellular ATP and modulated positively by extracellular zinc. On the basis of these results, we propose that, within endocrine pancreatic islets, secreted ATP and zinc have profound autocrine regulatory influence on insulin secretion via ATP-gated and zinc-modulated P2XR channels.


ATP Zinc P2X receptor channels Insulin secretion Islets β-cells 



Adenosine 5′ triphosphate


Adenosine 5′ diphosphate


Adenosine 5′ monophosphate






Intracellular calcium concentration


Diethylene triamine pentaacetic acid


HEPES balanced salt solution


Islet of Langerhans

K+ATP channel

Sulphonylurea receptor (SUR) and KIR 6.2 channel complex


P2X purinergic receptor channels


P2Y purinergic G protein-coupled receptors




Voltage-activated calcium channels



We gratefully acknowledge the funding support of the Juvenile Diabetes Research Foundation (Innovation Grant 5-2007-262 to E.M.S.) and grants of our islet isolation collaborator, Dr. Juan Contreras, M.D. Dr. Contreras is director of the Southern Tissue Center, a funded provider of islets for the southeastern U/S. We thank Cheryl A. Smyth, MS, and Stacie Jenkins-Bryant, BA, colleagues of Dr. Contreras, who were very generous with their time, efforts, and education with regard to islet isolation. Dr. Contreras’s entire group was very generous with time and resources for this study. We also thank Dr. Susan Bellis, Ph.D., and Kristin Hennessy for assistance with and use of the fluorescence microscope. We thank Nai-Lin Cheng for help with molecular biology and biochemistry. We thank Dr. Lydia Aguilar-Bryan for tireless encouragement for entering the field of islet cell biology and diabetes. C.R.W. is supported by an NRSA Predoctoral Fellowship (5 F31 GM078758-02). We acknowledge previous support from the American Physiological Society (APS) in the form of an APS Porter Fellowship. C.R.W. is also currently a Fellow for the APS NIDDK K-12 Minority Outreach Program.


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Copyright information

© Springer Science+Business Media B.V. 2008

Authors and Affiliations

  • Clintoria Richards-Williams
    • 1
  • Juan L. Contreras
    • 2
  • Kathleen H. Berecek
    • 1
  • Erik M. Schwiebert
    • 1
    • 3
    Email author
  1. 1.Department of Physiology and BiophysicsUniversity of Alabama at BirminghamBirminghamUSA
  2. 2.Department of SurgeryUniversity of Alabama at BirminghamBirminghamUSA
  3. 3.DiscoveryBioMed, Inc.BirminghamUSA

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