HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) Submit a Letter to Editor Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map 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 Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Bevan, A. P. Articles by Smith, G. D. Search for Related Content PubMed PubMed Citation Articles by Bevan, A. P. Articles by Smith, G. D. Social Bookmarking                      What's this?

Volume 272, Number 43, Issue of October 24, 1997 pp. 26833-26840
©1997 by The American Society for Biochemistry and Molecular Biology, Inc.

Chloroquine Extends the Lifetime of the Activated Insulin Receptor Complex in Endosomes

(Received for publication, July 8, 1997)

From the Department of Clinical Biochemistry, University of Cambridge, Addenbrooke's Hospital, Hills Road, Cambridge CB2 2QR, United Kingdom

Insulin signal transduction, initiated by binding of insulin to its receptor at the plasma membrane, activates the intrinsic receptor tyrosine kinase and leads to internalization of the activated ligand-receptor complex into endosomes. This study addresses the role played by the activated insulin receptor within hepatic endosomes and provides evidence for its central role in insulin-stimulated events in vivo. Rats were treated with chloroquine, an acidotrophic agent that has been shown previously to inhibit endosomal insulin degradation, and then with insulin. Livers were removed and fractionated by density gradient centrifugation to obtain endosomal and plasma membrane preparations. Chloroquine treatment increased the amount of receptor-bound insulin in endosomes at 2 min after insulin injection by 93% as determined by exclusion from G-50 columns and by 90% as determined by polyethylene glycol precipitation (p < 0.02). Chloroquine treatment also increased the insulin receptor content of endosomes after insulin injection (integrated over 0-45 min) by 31% when compared with controls (p < 0.05). Similarly, chloroquine increased both insulin receptor phosphotyrosine content and its exogenous tyrosine kinase activity after insulin injection (64%; p < 0.01 and 96% and p < 0.001, respectively). In vivo chloroquine treatment was without any observable effect on insulin binding to plasma membrane insulin receptors, nor did it augment insulin-stimulated receptor autophosphorylation or kinase activity in the plasma membrane. Concomitant with its effects on endosomal insulin receptors, chloroquine treatment augmented insulin-stimulated incorporation of glucose into glycogen in diaphragm (p < 0.001). These observations are consistent with the hypothesis that chloroquine-dependent inhibition of endosomal insulin receptor dissociation and subsequent degradation prolongs the half-life of the active endosomal receptor and potentiates insulin signaling from this compartment.

CiteULike    Complore    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this?

This article has been cited by other articles:

				I N Bruce The influence of other drugs on coronary heart disease (CHD) risk in systemic lupus erythematosus Lupus, November 1, 2006; 15(11_suppl): 23 - 26. [Abstract] [PDF]

				I. N. Bruce 'Not only...but also': factors that contribute to accelerated atherosclerosis and premature coronary heart disease in systemic lupus erythematosus Rheumatology, December 1, 2005; 44(12): 1492 - 1502. [Abstract] [Full Text] [PDF]

				I N Bruce Atherogenesis and autoimmune disease: the model of lupus Lupus, September 1, 2005; 14(9): 687 - 690. [Abstract] [PDF]

				A. Balbis, G. Baquiran, V. Dumas, and B. I. Posner Effect of Inhibiting Vacuolar Acidification on Insulin Signaling in Hepatocytes J. Biol. Chem., March 26, 2004; 279(13): 12777 - 12785. [Abstract] [Full Text] [PDF]

				T. Ogata Increase in epidermal growth factor receptor protein induced in osteoblastic cells after exposure to flow of culture media Am J Physiol Cell Physiol, August 1, 2003; 285(2): C425 - C432. [Abstract] [Full Text] [PDF]

				M.-C. Ma, H.-S. Huang, M.-S. Wu, C.-T. Chien, and C.-F. Chen Impaired Renal Sensory Responses after Renal Ischemia in the Rat J. Am. Soc. Nephrol., July 1, 2002; 13(7): 1872 - 1883. [Abstract] [Full Text] [PDF]

				A. Balbis, G. Baquiran, J. J. M. Bergeron, and B. I. Posner Compartmentalization and Insulin-Induced Translocations of Insulin Receptor Substrates, Phosphatidylinositol 3-Kinase, and Protein Kinase B in Rat Liver Endocrinology, November 1, 2000; 141(11): 4041 - 4049. [Abstract] [Full Text] [PDF]

				A. W. Kao, B. P. Ceresa, S. R. Santeler, and J. E. Pessin Expression of a Dominant Interfering Dynamin Mutant in 3T3L1 Adipocytes Inhibits GLUT4 Endocytosis without Affecting Insulin Signaling J. Biol. Chem., September 25, 1998; 273(39): 25450 - 25457. [Abstract] [Full Text] [PDF]

				J.-O. Contreres, R. Faure, G. Baquiran, J. J. Bergeron, and B. I. Posner ATP-dependent Desensitization of Insulin Binding and Tyrosine Kinase Activity of the Insulin Receptor Kinase. THE ROLE OF ENDOSOMAL ACIDIFICATION J. Biol. Chem., August 21, 1998; 273(34): 22007 - 22013. [Abstract] [Full Text] [PDF]

				J. C. Zwaagstra, M. El-Alfy, and M. D. O'Connor-McCourt Transforming Growth Factor (TGF)-beta 1 Internalization. MODULATION BY LIGAND INTERACTION WITH TGF-beta RECEPTORS TYPES I AND II AND A MECHANISM THAT IS DISTINCT FROM CLATHRIN-MEDIATED ENDOCYTOSIS J. Biol. Chem., July 13, 2001; 276(29): 27237 - 27245. [Abstract] [Full Text] [PDF]