Differential regulation of RhoA-mediated signaling by the TP alpha and TP beta isoforms of the human thromboxane A2 receptor: Independent modulation of TP alpha signaling by prostacyclin and nitric oxide

摘要

In humans, thromboxane (TX) A(2) signals through the TP alpha and TP beta isoforms of the TXA(2) receptor that exhibit common and distinct roles. For example, Gq/phospholipase (PL)C beta signaling by TP alpha is directly inhibited by the vasodilators prostacyclin and nitric oxide (NO) whereas that signaling by TP beta is unaffected. Herein, we investigated whether TPa and/or TP beta regulate G(12)/Rho activation and whether that signaling might be differentially regulated by prostacyclin and/or NO. Both TP alpha and TP beta independently regulated RhoA activation and signaling in clonal cells over-expressing TP alpha or TP beta and in primary human aortic smooth muscle cells (1 degrees AoSMCs). While RhoA-signaling by TP alpha was directly impaired by prostacyclin and NO through protein kinase (PK)A- and PKG-dependent phosphorylation, respectively, signaling by TP beta was not directly affected by either agent. Collectively, while TP alpha and TP beta contribute to RhoA activation, our findings support the hypothesis that TP alpha is involved in the dynamic regulation of haemostasis and vascular tone, such as in response to prostacyclin and NO. Conversely, the role of TP beta in such processes remains unsolved. Data herein provide essential new insights into the physiologic roles of TP alpha and TP beta and, through studies in AoSMCs, reveal an additional mode of regulation of VSM contractile responses by TXA2. (c) 2008 Elsevier Inc. All rights reserved.