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J. Biol. Chem., Vol. 279, Issue 13, 12777-12785, March 26, 2004

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Effect of Inhibiting Vacuolar Acidification on Insulin Signaling in Hepatocytes^*

Alejandro Balbis, Gerardo Baquiran, Victor Dumas, and Barry I. Posner

From the Polypeptide Hormone Laboratory, Faculty of Medicine, McGill University, Montreal, Quebec H3A 2B2, Canada

Previous studies have shown that the endosomal apparatus plays an important role in insulin signaling. Inhibition of endosomal acidification leads to a decrease in insulin-insulin receptor kinase (IRK) dissociation and insulin degradation. Thus, vacuolar pH could function as a modulator of insulin signaling in endosomes. In the present study we show that in primary hepatocytes pretreated with bafilomycin, there is an inhibition of vacuolar acidification. Incubation of these cells with insulin was followed by an augmentation of IRK activity but an inhibition of phosphatidylinositol 3-kinase/Akt activity and a decrease in insulin-induced DNA and glycogen synthesis. Bafilomycin treatment inhibited IRK recycling to the plasma membrane without affecting IRK internalization. Impaired IRK recycling correlated with a decrease in insulin signaling. We suggest that inhibiting vacuolar acidification sequesters activated IRKs in an intracellular compartment(s) where signaling is inhibited. This implies that endosomal receptor trafficking plays a role in regulating signal transduction.

Received for publication, October 20, 2003 , and in revised form, December 4, 2003.

^* This work was supported by grants from the Canadian Institutes of Health Research and the National Cancer Institute of Canada and by ongoing support from the Cleghorn Research Fund at McGill University and the Maurice Pollack Foundation of Montreal. 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.

To whom correspondence should be addressed: Polypeptide Hormone Laboratory, Faculty of Medicine, McGill University, 3640 University St., Ste. W315, Montreal, PQ H3A 2B2, Canada. Tel.: 514-398-4101; Fax: 514-398-3923; E-mail: barry.posner{at}staff.mcgill.ca.

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