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

摘要

In humans, thromboxane (TX) A2 signals through theTPα and TPβ isoforms of the TXA2 receptor that exhibit commonand distinct roles. For example, Gq/phospholipase (PL)Cβ signaling by TPα isdirectly inhibited by the vasodilators prostacyclin and nitric oxide (NO)whereas that signaling by TPβ is unaffected. Herein, we investigated whether TPαand/or TPβ regulate G12/Rho activation and whether thatsignaling might be differentially regulated by prostacyclin and/or NO. Both TPαand TPβ independently regulated RhoA activation and signaling in clonal cellsover-expressing TPα or TPβ and in primary human aortic smooth muscle cells (1°AoSMCs). While RhoA-signaling by TPα was directly impaired by prostacyclin andNO through protein kinase (PK)A- and PKG-dependent phosphorylation,respectively, signaling by TPβ was not directly affected by either agent.Collectively, while TPα and TPβ contribute to RhoA activation, our findingssupport the hypothesis that TPα is involved in the dynamic regulation ofhaemostasis and vascular tone, such as in response to prostacyclin and NO.Conversely, the role of TPβ in such processes remains unsolved. Data hereinprovide essential new insights into the physiologic roles of TPα and TPβ and,through studies in AoSMCs, reveal an additional mode of regulation of VSMcontractile responses by TXA2.