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J. Biol. Chem., Vol. 282, Issue 34, 24538-24546, August 24, 2007

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Glucose-induced Cytosolic pH Changes in -Cells and Insulin Secretion Are Not Causally Related

STUDIES IN ISLETS LACKING THE NA⁺/H⁺ EXCHANGER NHE1^*

Patrick Stiernet¹, Myriam Nenquin, Pierre Moulin, Jean-Christophe Jonas², and Jean-Claude Henquin³

From the Units of Endocrinology and Metabolism and Pathology, University of Louvain Faculty of Medicine, UCL 55.30, B-1200 Brussels, Belgium

The contribution of Na⁺/H⁺ exchange (achieved by NHE proteins) to the regulation of -cell cytosolic pH_c, and the role of pH_c changes in glucose-induced insulin secretion are disputed and were examined here. Using real-time PCR, we identified plasmalemmal NHE1 and intracellular NHE7 as the two most abundant NHE isoforms in mouse islets. We, therefore, compared insulin secretion, cytosolic free Ca²⁺ ([Ca²⁺]_c) and pH_c in islets from normal mice and mice bearing an inactivating mutation of NHE1 (Slc9A1-swe/swe). The experiments were performed in HCO^–₃/CO₂ or HEPES/NaOH buffers. PCR and functional approaches showed that NHE1 mutant islets do not express compensatory pH-regulating mechanisms. NHE1 played a greater role than HCO^–₃-dependent mechanisms in the correction of an acidification imposed by a pulse of NH₄Cl. In contrast, basal pH_c (in low glucose) and the alkalinization produced by high glucose were independent of NHE1. Dimethylamiloride, a classic blocker of Na⁺/H⁺ exchange, did not affect pH_c but increased insulin secretion in NHE1 mutant islets, indicating unspecific effects. In control islets, glucose similarly increased [Ca²⁺]_c and insulin secretion in HCO^–₃ and HEPES buffer, although pH_c changed in opposite directions. The amplification of insulin secretion that glucose produces when [Ca²⁺]_c is clamped at an elevated level by KCl was also unrelated to pH_c and pH_c changes. All effects of glucose on [Ca²⁺]_c and insulin secretion proved independent of NHE1. In conclusion, NHE1 protects -cells against strong acidification, but has no role in stimulus-secretion coupling. The changes in pH_c produced by glucose involve HCO^–₃-dependent mechanisms. Variations in -cell pH_c are not causally related to changes in insulin secretion.

Received for publication, April 4, 2007 , and in revised form, June 27, 2007.

^* This work was supported in part by the Fonds de la Recherche Scientifique Médicale (Grant 3.4552.04), the Belgian Science Policy (Grants PAI 5/17 and PAI 6/40), and the Direction de la Recherche Scientifique of the French Community of Belgium (Grant ARC 05/10-328). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ Aspirant of the Fonds National de la Recherche Scientifique, Brussels.

² Senior Research Associate of the Fonds National de la Recherche Scientifique, Brussels.

³ To whom correspondence should be addressed: Unité d'Endocrinologie et Métabolisme, UCL 55.30, Ave. Hippocrate 55, B-1200 Brussels, Belgium. Tel.: 32-2-7645529; Fax: 32-2-7645532; E-mail: henquin{at}endo.ucl.ac.be.

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