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J. Biol. Chem., Vol. 281, Issue 29, 19995-20002, July 21, 2006

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Transforming Growth Factor Regulates the Expression of the M₂ Muscarinic Receptor in Atrial Myocytes via an Effect on RhoA and p190RhoGAP^*

Ho-Jin Park¹², Simone M. Ward¹, Jay S. Desgrosellier^¶13, Serban P. Georgescu¹, Alexander G. Papageorge^||, Xiaoli Zhuang, Joey V. Barnett^¶, and Jonas B. Galper⁴

From the Molecular Cardiology Research Institute, Department of Medicine, Tufts New England Medical Center and Tufts University School of Medicine, Boston, Massachusetts 02111, the Cardiovascular Division, Brigham and Women's Hospital, Boston, Massachusetts 02115, the ^¶Department of Pharmacology, Vanderbilt University School of Medicine, Nashville, Tennessee 37232, and the ^||NCI, National Institutes of Health, Bethesda, Maryland 20892

Transforming growth factor (TGF) signaling is involved in the development and regulation of multiple organ systems and cellular signaling pathways. We recently demonstrated that TGF regulates the response of atrial myocytes to parasympathetic stimulation. Here, TGF₁ is shown to inhibit expression of the M₂ muscarinic receptor (M₂), which plays a critical role in the parasympathetic response of the heart. This effect is mimicked by overexpression of a dominant negative mutant of RhoA and by the RhoA kinase inhibitor Y27632, whereas adenoviral expression of a dominant activating-RhoA reverses TGF inhibition of M₂ expression. TGF₁ also mediates a decrease in GTP-bound RhoA and a reciprocal increase in the expression of the RhoA GTPase-activating protein, p190RhoGAP, whereas total RhoA is unchanged. Inhibition of M₂ promoter activity by TGF₁ is mimicked by overexpression of p190RhoGAP, whereas a dominant negative mutant of p190RhoGAP reverses this effect of TGF₁. In contrast to atrial myocytes, in mink lung epithelial cells, in which TGF signaling through activation of RhoA has been previously identified, TGF₁ stimulated an increase in GTP-bound RhoA in association with a reciprocal decrease in the expression of p190RhoGAP. Both effects demonstrated a similar dose dependence on TGF₁. Thus TGF regulation of M₂ muscarinic receptor expression is dependent on RhoA, and TGF regulation of p190RhoGAP expression may be a cell type-specific mechanism for TGF signaling through RhoA.

Received for publication, December 8, 2005 , and in revised form, April 13, 2006.

^* This work was supported in part by National Institutes of Health Grants HL54225 and HL66467 (to J. B. G.) and HL52922 (to J. V. B.). 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.

¹ These authors contributed equally to this work.

³ Supported by a predoctoral fellowship from the Pharmaceutical Research and Manufacturers of America Foundation.

² A recipient of a Scientist Development Grant from the American Heart Association. To whom correspondence may be addressed. Tel.: 617-636-9005; E-mail: hpark{at}tufts-nemc.org. ⁴ To whom correspondence may be addressed. Tel.: 617-636-9004; E-mail: jgalper{at}tufts-nemc.org.

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