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This Article Full Text Full Text (PDF) Supplemental Data All Versions of this Article: 563/1/161    most recent jphysiol.2004.076414v1 Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Reimann, F Articles by Gribble, F. M Search for Related Content PubMed PubMed Citation Articles by Reimann, F Articles by Gribble, F. M

¹ Cambridge Institute for Medical Research, University of Cambridge, Department of Clinical Biochemistry, Wellcome Trust/MRC Building, Addenbrooke's Hospital, Hills Road, Cambridge CB2 2XY, UK
² Banting and Best Diabetes Centre, University of Toronto, Toronto General Hospital, 200 Elizabeth Street MBRW-4R402, Toronto, Canada M5G 2C4

Glucagon-like peptide-1 (GLP-1) is released from intestinal L-cells in response to nutrient ingestion. It is currently under therapeutic evaluation because it enhances insulin secretion in type 2 diabetes. Previous studies using the GLP-1 secreting cell line GLUTag have shown that the cells are electrically active, and that the action potential frequency is regulated by nutrients. In this study we characterize voltage gated currents underlying this electrical activity and correlate the electrophysiological findings with gene expression determined by microarrays. Whole cell voltage clamp experiments designed to separate different ionic components revealed rapidly inactivating sodium currents sensitive to tetrodotoxin, calcium currents sensitive to nifedipine and -conotoxin GVIA, and sustained as well as rapidly inactivating potassium currents, which were sensitive to TEA and 4-AP, respectively. In perforated patch experiments we also observed hyperpolarization-activated currents which were inhibited by ZD7288. The amplitude of the sodium current was 10 times that of the other depolarizing currents and tetrodotoxin abolished action potential firing. In secretion experiments, however, nifedipine, but not tetrodotoxin, -conotoxin GVIA or ZD7288, inhibited glucose-induced GLP-1 release. Consistent with this finding, the intracellular Ca²⁺ response to glucose was impaired by nifedipine but not by tetrodotoxin. Thus, in GLUTag cells, GLP-1 release is not dependent on the firing of Na⁺-carrying action potentials but requires membrane depolarization and Ca²⁺ entry through L-type Ca²⁺ channels. Understanding the characteristics of the currents and the molecular identification of the underlying channels in GLP-1 secreting cells might facilitate the development of agents to enhance GLP-1 secretion in vivo.

(Received 30 September 2004; accepted after revision 15 December 2004; first published online 20 December 2004)
Corresponding author F. Reimann: Cambridge Institute for Medical Research, University of Cambridge, Department of Clinical Biochemistry, Wellcome Trust/MRC Building, Addenbrooke's Hospital, Hills Road, Cambridge CB2 2XY, UK. Email: fr222{at}cam.ac.uk

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				F. Reimann, P. S. Ward, and F. M. Gribble Signaling Mechanisms Underlying the Release of Glucagon-Like Peptide 1 Diabetes, December 1, 2006; 55(Supplement_2): S78 - S85. [Abstract] [Full Text] [PDF]

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