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Inhibition of connexin 36 hemichannels by glucose contributes to the stimulation of insulin secretion.
- Source :
-
American Journal of Physiology: Endocrinology & Metabolism . Jun2014, Vol. 306 Issue 12, pE1354-E1366. 13p. - Publication Year :
- 2014
-
Abstract
- The existence of functional connexin36 (Cx36) hemichannels in β-cells was investigated in pancreatic islets of rat and wild-type (Cx36+/+), monoallelic (Cx36+/-), and biallelic (Cx36-/-) knockout mice. Hemichannel opening by KCl depolarization was studied by measuring ATP release and changes of intracellular ATP (ADP). Cx36+/+ islets lost ATP after depolarization with 70 mM KCl at 5 mM glucose; ATP loss was prevented by 8 and 20 mM glucose or 50 μM mefloquine (connexin inhibitor). ATP content was higher in Cx36-/- than Cx36+/+ islets and was not decreased by KCl depolarization; Cx36+/- islets showed values between that of control and homozygous islets. Five minimolar extracellular ATP increased ATP content and ATP/ADP ratio and induced a biphasic insulin secretion in depolarized Cx36+/+ and Cx36+/- but not Cx36-/- islets. Cx36 hemichannels expressed in oocytes opened upon depolarization of membrane potential, and their activation was inhibited by mefloquine and glucose (IC50 ∼8 mM). It is postulated that glucose-induced inhibition of Cx36 hemichannels in islet β-cells might avoid depolarization-induced ATP loss, allowing an optimum increase of the ATP/ADP ratio by sugar metabolism and a biphasic stimulation of insulin secretion. Gradual suppression of glucose-induced insulin release in Cx36+/- and Cx36-/- islets confirms that Cx36 gap junction channels are necessary for a full secretory stimulation and might account for the glucose intolerance observed in mice with defective Cx36 expression. Mefloquine targeting of Cx36 on both gap junctions and hemichannels also suppresses glucose-stimulated secretion. By contrast, glucose stimulation of insulin secretion requires Cx36 hemichannels' closure but keeping gap junction channels opened. [ABSTRACT FROM AUTHOR]
Details
- Language :
- English
- ISSN :
- 01931849
- Volume :
- 306
- Issue :
- 12
- Database :
- Academic Search Index
- Journal :
- American Journal of Physiology: Endocrinology & Metabolism
- Publication Type :
- Academic Journal
- Accession number :
- 98542048
- Full Text :
- https://doi.org/10.1152/ajpendo.00358.2013