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

J. Biol. Chem., Vol. 279, Issue 5, 3254-3264, January 30, 2004

This Article Full Text Full Text (PDF) All Versions of this Article: 279/5/3254    most recent M305474200v1 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 Ferreira, I. A. Articles by Akkerman, J.-W. N. Search for Related Content PubMed PubMed Citation Articles by Ferreira, I. A. Articles by Akkerman, J.-W. N. Social Bookmarking                      What's this?

IRS-1 Mediates Inhibition of Ca²⁺ Mobilization by Insulin via the Inhibitory G-protein G_i^*

Irlando Andrade Ferreira, Kurt L. Eybrechts, Astrid I. M. Mocking, Christine Kroner¶, and Jan-Willem N. Akkerman||

From the Thrombosis and Haemostasis Laboratory, Department of Hematology, University Medical Center Utrecht, Heidelberlaan 100, 3584 CX Utrecht, The Netherlands, Institute for Biomembranes, Utrecht University, Padualaan 8, 3584 CH Utrecht, The Netherlands, and ^¶Unilever Health Institute, Unilever Research and Development, 3133 AT Vlaardingen, The Netherlands

Platelet agonists initiate aggregation and secretion by activating receptors coupled to the G-protein G_q, thereby raising cytosolic Ca²⁺, [Ca²⁺]_i. The rise in [Ca²⁺]_i is facilitated via inhibition of cAMP formation by the inhibitory G-protein of adenylyl cyclase, G_i. Since insulin attenuates platelet activation, we investigated whether insulin interferes with cAMP regulation. Here we report that insulin (0.5–200 nmol/liter) interferes with agonist-induced increases in [Ca²⁺]_i (ADP, thrombin), cAMP suppression (thrombin), and aggregation (ADP). The effects of insulin are as follows: (i) independent of the P2Y₁₂ receptor, which mediates ADP-induced cAMP lowering; (ii) not observed during G_s-mediated cAMP formation; (iii) unaffected by treatments that affect phosphodiesterases (3-isobutyl-1-methylxanthine); and (iv) not changed by interfering with NO-mediated regulation of cAMP degradation (N^G-monomethyl-L-arginine). Hence, insulin might interfere with G_i. Indeed, insulin induces the following: (i) tyrosine phosphorylation of the insulin receptor, the insulin receptor substrate-1 (IRS-1) and G_i2; (ii) co-precipitation of IRS-1 with G_i2 but not with other G subunits. Despite persistent receptor activation, the association of IRS-1 with G_i2 is transient, being optimal at 5 min and 1 nmol/liter insulin, which is sufficient to suppress Ca²⁺ signaling by ADP, and at 10 min and 100 nmol/liter insulin, which is required to suppress Ca²⁺ signaling by thrombin. Epinephrine, a known platelet sensitizer and antagonist of insulin, abolishes the effect of insulin on [Ca²⁺]_i, tyrosine phosphorylation of G_i2, and aggregation by interfering with the phosphorylation of the insulin receptor subunit. We conclude that insulin attenuates platelet functions by interfering with cAMP suppression through IRS-1 and G_i.

Received for publication, May 24, 2003 , and in revised form, October 13, 2003.

^* This work was supported in part by Dutch Diabetes Research Foundation Grant 1999-046. 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.

^|| Supported by the Netherlands Thrombosis Foundation. To whom correspondence should be addressed: Thrombosis and Haemostasis Laboratory, Dept. of Hematology, University Medical Center Utrecht, Heidelberglaan 100, 3584 CX Utrecht, The Netherlands. Tel.: 31-30-250-7613; Fax: 31-30-251-1893; E-mail: i.a.ferreira{at}lab.azu.nl.

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

This article has been cited by other articles:

				D. J. Schneider Factors Contributing to Increased Platelet Reactivity in People With Diabetes Diabetes Care, April 1, 2009; 32(4): 525 - 527. [Full Text] [PDF]

				V. Randriamboavonjy and I. Fleming Insulin, Insulin Resistance, and Platelet Signaling in Diabetes Diabetes Care, April 1, 2009; 32(4): 528 - 530. [Full Text] [PDF]

				D. J. Angiolillo Antiplatelet Therapy in Diabetes: Efficacy and Limitations of Current Treatment Strategies and Future Directions Diabetes Care, April 1, 2009; 32(4): 531 - 540. [Full Text] [PDF]

				S. D. Wiviott, E. Braunwald, D. J. Angiolillo, S. Meisel, A. J. Dalby, F. W.A. Verheugt, S. G. Goodman, R. Corbalan, D. A. Purdy, S. A. Murphy, et al. Greater Clinical Benefit of More Intensive Oral Antiplatelet Therapy With Prasugrel in Patients With Diabetes Mellitus in the Trial to Assess Improvement in Therapeutic Outcomes by Optimizing Platelet Inhibition With Prasugrel-Thrombolysis in Myocardial Infarction 38 Circulation, October 14, 2008; 118(16): 1626 - 1636. [Abstract] [Full Text] [PDF]

				D. J. Angiolillo, P. Capranzano, S. Goto, M. Aslam, B. Desai, R. K. Charlton, Y. Suzuki, L. C. Box, S. B. Shoemaker, M. M. Zenni, et al. A randomized study assessing the impact of cilostazol on platelet function profiles in patients with diabetes mellitus and coronary artery disease on dual antiplatelet therapy: results of the OPTIMUS-2 study Eur. Heart J., September 2, 2008; 29(18): 2202 - 2211. [Abstract] [Full Text] [PDF]

				C. Manrique, G. Lastra, J. Palmer, M. Gardner, and J. R. Sowers Review: Aspirin and Diabetes Mellitus: revisiting an old player Therapeutic Advances in Cardiovascular Disease, February 1, 2008; 2(1): 37 - 42. [Abstract] [PDF]

				I. Hers Insulin-like growth factor-1 potentiates platelet activation via the IRS/PI3K{alpha} pathway Blood, December 15, 2007; 110(13): 4243 - 4252. [Abstract] [Full Text] [PDF]

				D. J. Angiolillo, S. B. Shoemaker, B. Desai, H. Yuan, R. K. Charlton, E. Bernardo, M. M. Zenni, L. A. Guzman, T. A. Bass, and M. A. Costa Randomized Comparison of a High Clopidogrel Maintenance Dose in Patients With Diabetes Mellitus and Coronary Artery Disease: Results of the Optimizing Antiplatelet Therapy in Diabetes Mellitus (OPTIMUS) Study Circulation, February 13, 2007; 115(6): 708 - 716. [Abstract] [Full Text] [PDF]

				D. J. Angiolillo, E. Bernardo, C. Ramirez, M. A. Costa, M. Sabate, P. Jimenez-Quevedo, R. Hernandez, R. Moreno, J. Escaned, F. Alfonso, et al. Insulin Therapy Is Associated With Platelet Dysfunction in Patients With Type 2 Diabetes Mellitus on Dual Oral Antiplatelet Treatment J. Am. Coll. Cardiol., July 18, 2006; 48(2): 298 - 304. [Abstract] [Full Text] [PDF]

				B. J. Goldstein, K. Mahadev, and X. Wu Redox Paradox: Insulin Action Is Facilitated by Insulin-Stimulated Reactive Oxygen Species With Multiple Potential Signaling Targets Diabetes, February 1, 2005; 54(2): 311 - 321. [Abstract] [Full Text] [PDF]