The α, but Not the β, Isoform of the Human Thromboxane A2 Receptor Is a Target for Prostacyclin-mediated Desensitization

Abstract

In this study, we examined the effects the prostacyclin receptor (IP) agonist cicaprost exhibited on U46619-mediated thromboxane A 2 receptor (TP) signaling in platelets and compared it to that which occurs in human embryonic kidney (

Thromboxane A2 Signalling in Humans: a ‘Tail’ of Two Receptors

“…Figure 5D]. Subsequent, whole cell phosphorylation assays confirmed that TPα, but not TPβ or TPα S329A , is indeed a direct target of cicaprost / IPmediated PKA phosphorylation [62]. Thus, these studies confirm that TPα, but not TPβ, is subject to counter regulation or heterologous desensitization by IP, mediated through direct PKA phosphorylation within the unique C-tail of TPα whereby Ser 329 has been identified as the target residue for phosphorylation.…”

“…Computational analyses of the unique C-tail domains of the TPα isoform indicated the presence of a putative PKA phosphorylation site within the sequence RS 329 LSL where Ser 329 is predicted to be the target residue for phosphorylation [62]. Figure 5D].…”

Heterodimerization of the α and β isoforms of the human thromboxane receptor enhances isoprostane signaling

“…i ) was assessed in stably transfected HEK cells, as previously described [14]. Cells were loaded for 1h at 37 o C with 5uM Fura-2/AM (Molecular Probes) in phenol red free-RPMI 1640 culture media.…”

The role of N-linked glycosylation in determining the surface expression, G protein interaction and effector coupling of the alpha (α) isoform of the human thromboxane A2 receptor

“…More recent reports show that both TPα and TPβ are subject to differential heterologous desensitization. For instance TPα, but not TPβ, is subject to cross-desensitization by prostacyclin, mediated through direct protein kinase (PK) A phosphorylation of TPα at Ser 329 ; these latter findings led to the proposal that TPα may be the isoform physiologically relevant to TP:prostacyclin receptor (IP)-mediated vascular hemostasis (8). Furthermore TPα, but not TPβ, is subject to prostaglandin (PG) D 2 receptor (DP)-mediated cross desensitization (9).…”