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Differential regulation of RhoA-mediated signaling by the TPalpha and TPbeta isoforms of the human thromboxane A2 receptor : independent modulation of TPalpha signaling by prostacyclin and nitric oxide
Wikström, Katarina; Kavanagh, David J.; Reid, Helen M.; Kinsella, B. Therese
In humans, thromboxane (TX) A2 signals through the TPalpha and TPbeta isoforms of the TXA2 receptor that exhibit common and distinct roles. For example, Gq/phospholipase (PL)Cbeta signaling by TPalpha is directly inhibited by the vasodilators prostacyclin and nitric oxide (NO) whereas that signaling by TPbeta is unaffected. Herein, we investigated whether TPalpha and/or TPbeta regulate G12/Rho activation and whether that signaling might be differentially regulated by prostacyclin and/or NO. Both TPalpha and TPbeta independently regulated RhoA activation and signaling in clonal cells over-expressing TPalpha or TPbeta and in primary human aortic smooth muscle cells (1o AoSMCs). While RhoA- signaling by TPalpha was directly impaired by prostacyclin and NO through protein kinase (PK)A- and PKG-dependent phosphorylation, respectively, signaling by TPbeta was not directly affected by either agent. Collectively, while TPalpha and TPbeta contribute to RhoA activation, our findings support the hypothesis that TPalpha is involved in the dynamic regulation of haemostasis and vascular tone, such as in response to prostacyclin and NO. Conversely, the role of TPbeta in such processes remains unsolved. Data herein provide essential new insights into the physiologic roles of TPalpha and TPbeta and, through studies in AoSMCs, reveal an additional mode of regulation of VSM contractile responses by TXA2. Science Foundation Ireland Health Research Board The Wellcome Trust
Keyword(s): Thromboxane receptor; RhoA; Nitric oxide; Prostacyclin; Protein kinase; Heterologous desensitization; Thromboxanes; Rho GTPases; Receptors, Thromboxane; rhoA GTP-Binding Protein; Nitric Oxide; Epoprostenol; Protein Kinases
Publication Date:
2011
Type: Journal article
Peer-Reviewed: Unknown
Language(s): English
Institution: University College Dublin
Publisher(s): Elsevier
File Format(s): other; application/pdf
First Indexed: 2012-08-25 05:17:30 Last Updated: 2018-10-11 16:26:07