Transforming Growth Factor beta Regulates the Expression of the M sub(2) Muscarinic Receptor in Atrial Myocytes via an Effect on RhoA and p190RhoGAP

Transforming growth factor beta (TGF beta ) signaling is involved in the development and regulation of multiple organ systems and cellular signaling pathways. We recently demonstrated that TGF beta regulates the response of atrial myocytes to parasympathetic stimulation. Here, TGF beta sub(1) is shown to inhibit expression of the M sub(2) muscarinic receptor (M sub(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 TGF beta inhibition of M sub(2) expression. TGF beta sub(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 sub(2) promoter activity by TGF beta sub(1) is mimicked by overexpression of p190RhoGAP, whereas a dominant negative mutant of p190RhoGAP reverses this effect of TGF beta sub(1). In contrast to atrial myocytes, in mink lung epithelial cells, in which TGF beta signaling through activation of RhoA has been previously identified, TGF beta sub(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 TGF beta sub(1). Thus TGF beta regulation of M sub(2) muscarinic receptor expression is dependent on RhoA, and TGF beta regulation of p190RhoGAP expression may be a cell type-specific mechanism for TGF beta signaling through RhoA.