Biochemical Pharmacology 2010-07-01

The signalling role of action potential depolarization in insulin secretion: metabolism-dependent dissociation between action potential increase and secretion increase by TEA.

M Willenborg, H Ghaly, K Hatlapatka, K Urban, U Panten, I Rustenbeck

Index: Biochem. Pharmacol. 80(1) , 104-12, (2010)

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Abstract

The K(+) channel blocker, TEA is known to increase action potential amplitude and insulin secretion of mouse beta-cells when added to a nutrient secretagogue. In the presence of a maximally effective sulfonylurea concentration (2.7 microM glipizide) the nutrient secretagogue alpha-ketoisocaproic acid (KIC, 10mM) strongly increased insulin secretion (about elevenfold). Instead of enhancing the effect of KIC, TEA reduced the KIC-induced secretion by more than 50%. Also, the secretion rate produced by 2.7 microM glipizide alone was significantly reduced by TEA. In contrast, TEA enhanced the insulinotropic effect of glipizide when a basal glucose concentration (5mM) was present. In the presence as well as in the absence of glucose glipizide produced a plateau depolarization with superimposed action potentials. Under both conditions, TEA increased the glipizide-induced action potential amplitude and further elevated the cytosolic free calcium concentration ([Ca(2+)](i)) with an oscillatory characteristic. These effects depended on the activity of L-type Ca(2+) channels, even though the effect of TEA differed from that of 1 microM of the Ca(2+) channel opener, Bay K8644, which primarily increased action potential duration. TEA did not negatively affect parameters of beta-cell energy metabolism (NAD(P)H fluorescence and ATP/ADP ratio), rather, it slightly increased NAD(P)H fluorescence. Apparently, TEA inhibits insulin secretion in the absence of glucose in spite of a persistent ability to block K(+) ion conductance. Thus, the signalling role of action potential depolarization in insulin secretion may require reconsideration and ion conductance-independent actions of K(+) channels may be involved in this paradox effect of TEA.(c) 2010 Elsevier Inc. All rights reserved.