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Interaction and Inhibitory Cross-Talk between Endothelin and ErbB Receptors in the Adult Heart

Molecular and Cellular Pharmacology Program and Department of Physiology, University of Wisconsin, Madison, Wisconsin

Endothelin-1 (ET-1) regulates contractility and growth of the mammalian heart by binding endothelin receptor type A (ET_A) and endothelin receptor type B (ET_B) G-protein-coupled receptors. To identify growth signaling pathways associated with ET-1 receptors in adult myocardium, a combined immunoprecipitation/proteomic analysis was performed. Signaling proteins believed to function downstream of ET_A such as G_q, phospholipase C-1, protein kinase C (PKC) , and PKC were identified in immunoprecipitates of ET_A by matrix-assisted laser desorption ionization/time of flight mass spectrometry. Also prominent were the growth factor receptor tyrosine kinases erbB2 and erbB4 and their downstream growth signaling effectors phosphoinositide-3 kinase (PI3 kinase), Akt, Raf-1, mitogen-activated protein kinase kinase (MEK), and extracellular signal-regulated kinase (Erk). Western blot analysis confirmed coimmunoprecipitation of erbB2/4, PI3 kinase, and Akt with ET_A, and confocal microscopy revealed their colocalization in cardiac transverse tubules (T-tubules). The erbB4 receptor ligand neuregulin-1 (NRG1) promoted erbB2/4 tryosine phosphorylation and Akt serine phosphorylation in ventricular myocytes, whereas treatment with ET-1 did not. This observation argues against ET-1 growth signaling occurring via erbB2/4 transactivation in adult myocardium. ET-1 did, however, stimulate Erk1/2 phosphorylation and substantially blunted several NRG1-mediated actions, including erbB2/4 phosphorylation, serine phosphorylation of Akt, and negative inotropy. This inhibitory cross-talk between ET_A and erbB2/4-Akt pathways was mimicked by a phorbol ester and blocked by pharmacological inhibition of PKC or MEK/Erk. The proteomic analysis and subsequent investigation of receptor cross-talk indicate that growth signaling between ET_A and erbB pathways is fundamentally different in adult versus neonatal cardiac myocytes. The results may be relevant to cardiomyopathies associated with 1) prolonged exposure to ET-1; 2) degeneration of T-tubules; and 3) therapies targeted at erbB2 inhibition.

Address correspondence to: Dr. Jeffery W. Walker, University of Wisconsin School of Medicine, 1300 University Avenue, Madison, WI 53706. E-mail: jwalker{at}physiology.wisc.edu

This article has been cited by other articles:

				K. Y. Chung, M. Kang, and J. W. Walker Contractile regulation by overexpressed ETA requires intact T tubules in adult rat ventricular myocytes Am J Physiol Heart Circ Physiol, May 1, 2008; 294(5): H2391 - H2399. [Abstract] [Full Text] [PDF]