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

J. Biol. Chem., Vol. 278, Issue 41, 40343-40351, October 10, 2003

This Article Full Text Full Text (PDF) All Versions of this Article: 278/41/40343    most recent M305964200v1 Alert me when this article is cited 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 Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Howes, A. L. Articles by Brown, J. H. Search for Related Content PubMed PubMed Citation Articles by Howes, A. L. Articles by Brown, J. H. Social Bookmarking                      What's this?

Akt-mediated Cardiomyocyte Survival Pathways Are Compromised by G_q-induced Phosphoinositide 4,5-Bisphosphate Depletion^*

Amy L. Howes , Jane F. Arthur , Tong Zhang, Shigeki Miyamoto, John W. Adams ¶, Gerald W. Dorn II ||, Elizabeth A. Woodcock  and Joan Heller Brown **

From the Department of Pharmacology, University of California, San Diego, La Jolla, California 92093, ^¶Arena Pharmaceuticals, San Diego, California 92121, Cellular Biochemistry Laboratory, Baker Heart Research Institute, Melbourne, Victoria, Australia, and ^||Department of Internal Medicine, Division of Cardiology, University of Cincinnati Medical Center, Cincinnati, Ohio 45267

Expression of the wild type subunit of G_q (G_qWT) in cardiomyocytes induces hypertrophy, whereas a constitutively active G_q subunit (G_qQ209L) induces apoptosis. Akt phosphorylation increases with G_qWT expression but is markedly attenuated in cardiomyocytes expressing G_qQ209L or in those expressing G_qWT and treated with agonist. A membrane-targeted Akt rescues G_qQ209L-expressing cardiomyocytes from apoptotic cell death. In contrast, leukemia inhibitory factor fails to activate Akt or promote cell survival in these cells. Association of Akt and PDK-1 with the membrane is also diminished in G_qQ209L-expressing cardiomyocytes. Phosphatidylinositol 3,4,5-trisphosphate (PIP₃), the primary regulator of Akt, increases significantly in G_qWT-expressing cells but not in cardiomyocytes expressing G_qQ209L. Levels of phosphatidylinositol 4,5-bisphosphate (PIP₂), the immediate precursor of PIP₃, are also markedly lower in G_qQ209L-expressing compared to control cells. Expression of a G_qQ209L mutant that has diminished capacity to activate phospholipase C does not decrease PIP₂ or Akt or induce apoptosis. In transgenic mice with cardiac G_q overexpression, heart failure and increased cardiomyocyte apoptosis develop during the peripartal period. Akt phosphorylation and PIP₂ levels decrease concomitantly. Our findings suggest that an Akt-mediated cell survival pathway is compromised by the diminished availability of PIP₂ elicited by pathological levels of G_q activity.

Received for publication, June 6, 2003 , and in revised form, July 29, 2003.

^* This work was supported in part by NHLBI Grants HL28143 and HL46345 (to J. H. B.) and HL59888 (to G. W. D.) from the National Institutes of Health and by the Australian National Health and Medical Research Council (to E. A. W.). Some of this work was performed under the auspices of an international exchange program between the NHLBI, National Institutes of Health, and the Baker Research Institute (granted to J. H. B. and E. A. W.). 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 a National Institutes of Health Pharmacology Training Grant GM-07752 and currently an American Heart Association Predoctoral Fellow.

^** To whom correspondence should be addressed: Dept. of Pharmacology, University of California, San Diego, 9500 Gilman Dr., Mail Code 0636, La Jolla, CA 92093. Tel.: 858-534-2595; Fax: 858-534-4337; E-mail: jhbrown{at}ucsd.edu.

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

This article has been cited by other articles:

				E. A. Woodcock, X.-J. Du, M. E. Reichelt, and R. M. Graham Cardiac {alpha}1-adrenergic drive in pathological remodelling Cardiovasc Res, February 1, 2008; 77(3): 452 - 462. [Abstract] [Full Text] [PDF]

				S. Taboubi, J. Milanini, E. Delamarre, F. Parat, F. Garrouste, G. Pommier, J. Takasaki, J.-C. Hubaud, H. Kovacic, and M. Lehmann G{alpha}(q/11)-coupled P2Y2 nucleotide receptor inhibits human keratinocyte spreading and migration FASEB J, December 1, 2007; 21(14): 4047 - 4058. [Abstract] [Full Text] [PDF]

				G. W. Dorn II The Fuzzy Logic of Physiological Cardiac Hypertrophy Hypertension, May 1, 2007; 49(5): 962 - 970. [Full Text] [PDF]

				N. J. Evans and J. W. Walker Endothelin-1 Mobilizes Profilin-1-Bound PIP2 in Cardiac Muscle. Experimental Biology and Medicine, June 1, 2006; 231(6): 882 - 887. [Abstract] [Full Text] [PDF]

				S. Miyamoto, A. L. Howes, J. W. Adams, G. W. Dorn II, and J. H. Brown Ca2+ Dysregulation Induces Mitochondrial Depolarization and Apoptosis: ROLE OF Na+/Ca2+ EXCHANGER AND AKT J. Biol. Chem., November 18, 2005; 280(46): 38505 - 38512. [Abstract] [Full Text] [PDF]

				J.-M. Navenot, Z. Wang, M. Chopin, N. Fujii, and S. C. Peiper Kisspeptin-10-Induced Signaling of GPR54 Negatively Regulates Chemotactic Responses Mediated by CXCR4: a Potential Mechanism for the Metastasis Suppressor Activity of Kisspeptins Cancer Res., November 15, 2005; 65(22): 10450 - 10456. [Abstract] [Full Text] [PDF]

				R. D. Peavy, K. B. Hubbard, A. Lau, R. B. Fields, K. Xu, C. J. Lee, T. T. Lee, K. Gernert, T. J. Murphy, and J. R. Hepler Differential Effects of Gq{alpha}, G14{alpha}, and G15{alpha} on Vascular Smooth Muscle Cell Survival and Gene Expression Profiles Mol. Pharmacol., June 1, 2005; 67(6): 2102 - 2114. [Abstract] [Full Text] [PDF]

				E. Kobrinsky, S. Tiwari, V. A. Maltsev, J. B. Harry, E. Lakatta, D. R. Abernethy, and N. M. Soldatov Differential Role of the {alpha}1C Subunit Tails in Regulation of the Cav1.2 Channel by Membrane Potential, {beta} Subunits, and Ca2+ Ions J. Biol. Chem., April 1, 2005; 280(13): 12474 - 12485. [Abstract] [Full Text] [PDF]

				E. A. Woodcock Unc-II and Unc-III Are Cardioprotective against Ischemia Reperfusion Injury: An Essential Endogenous Cardioprotective Role for CRFR2 in the Murine Heart Endocrinology, January 1, 2004; 145(1): 21 - 23. [Full Text] [PDF]

				G. Fan, L. M. Ballou, and R. Z. Lin Phospholipase C-independent Activation of Glycogen Synthase Kinase-3{beta} and C-terminal Src Kinase by G{alpha}q J. Biol. Chem., December 26, 2003; 278(52): 52432 - 52436. [Abstract] [Full Text] [PDF]

				P. H. Sugden Ras, Akt, and Mechanotransduction in the Cardiac Myocyte Circ. Res., December 12, 2003; 93(12): 1179 - 1192. [Abstract] [Full Text] [PDF]