Transforming growth factor beta regulates the expression of the M2 muscarinic receptor in atrial myocytes via an effect on RhoA and p190RhoGAP.
Transforming growth factor beta (TGFbeta) signaling is involved in the development and regulation of multiple organ systems and cellular signaling pathways. We recently demonstrated that TGFbeta regulates the response of atrial myocytes to parasympathetic stimulation. Here, TGFbeta(1) is shown to inhibit expression of the M(2) muscarinic receptor (M(2)), 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 TGFbeta inhibition of M(2) expression. TGFbeta(1) 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 M(2) promoter activity by TGFbeta(1) is mimicked by overexpression of p190RhoGAP, whereas a dominant negative mutant of p190RhoGAP reverses this effect of TGFbeta(1). In contrast to atrial myocytes, in mink lung epithelial cells, in which TGFbeta signaling through activation of RhoA has been previously identified, TGFbeta(1) 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 TGFbeta(1). Thus TGFbeta regulation of M(2) muscarinic receptor expression is dependent on RhoA, and TGFbeta regulation of p190RhoGAP expression may be a cell type-specific mechanism for TGFbeta signaling through RhoA.
Park
Ho-Jin
HJ
Molecular Cardiology Research Institute, Department of Medicine, Tufts New England Medical Center, Tufts University School of Medicine, Boston, Massachusetts 02111, USA. hpark@tufts-nemc.org
Ward
Simone M
SM
Desgrosellier
Jay S
JS
Georgescu
Serban P
SP
Papageorge
Alexander G
AG
Zhuang
Xiaoli
X
Barnett
Joey V
JV
Galper
Jonas B
JB
D000577:Amides / Q000494:pharmacology; D000818:Animals; D002352:Carrier Proteins / Q000378:metabolism*; D002478:Cells, Cultured; D002642:Chick Embryo; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005786:Gene Expression Regulation / Q000187:drug effects; D006325:Heart Atria / Q000196:embryology; D032342:Muscle Cells / Q000187:drug effects / Q000502:physiology*; D011401:Promoter Regions, Genetic / Q000187:drug effects; D011725:Pyridines / Q000494:pharmacology; D043585:Receptor, Muscarinic M2 / Q000235:genetics*; D015398:Signal Transduction; D016212:Transforming Growth Factor beta / Q000494:pharmacology*; D020742:rhoA GTP-Binding Protein / Q000378:metabolism*
D000577:Amides; D002352:Carrier Proteins; D004791:Enzyme Inhibitors; D011725:Pyridines; D043585:Receptor, Muscarinic M2; D016212:Transforming Growth Factor beta; C108830:Y 27632; D020742:rhoA GTP-Binding Protein