TP receptor

Ramatroban is a PG receptor antagonist in use for the treatment of allergic rhinitis in Japan. This compound was initially identified as a TP receptor antagonist, although more recently it has been determined that it is also antagonizes the CRTH2 (DP2) receptor. 

TP receptor signaling has been extensively docnmented in vascnlar smooth mns-cle and platelets, but its characterization in hnman ASM cells has been more limited until recently. ASM cells express messenger RNA (mRNA) for both TP receptor isoforms, and functional receptors respond to agonist with an increase in intracellular Ca " concentration (200). As a consequence, besides potentiating the epidermal growth factor (EGF) mitogenic response independently from transactivation of the EGF receptor (EGER) (200), TP receptor stimulation induces a concentration-dependent increase in DNA synthesis. 

The TP receptor requires the G/G protein to activate the Src-Ras-ERKl/2 (extracellular signal-regulated kinase 1 and 2) cascade to induce the proliferative response, which in turn promotes the rapid nuclear translocation of activated ERKl/2 (201). Because TP receptor may be activated by many inflammatory mediators (202-204), these findings suggest new therapeutic strategies that alter the ASM hypertrophy or hyperplasia observed in the chronic airflow obstruction and airway inflammation that characterizes asthma, chronic bronchitis, bronchiolitis obliterans, and chronic obstructive pulmonary disease. 

The synthesis of selective CRTH2 receptor antagonists has been more extensively studied to develop them as potential clinical candidates for the treatment of allergy, asthma, or other inflammatory disorders (Fig. 10). Ramatroban, a TP receptor antagonist, clinically used in asthma and allergic rhinitis, was recently... 

TP receptors are widely distributed on arterial and venous vascular smooth muscle cells. TXAj-induced smooth muscle contraction mediates vasoconstriction (10,11) that is accoduated in the absence of endothelium (12). TXAj contributes to closure of umbilical vessels at birth (2). TXAj and TX analogs can induce or contribute to pulmonary hypertension (13-15) and systemic hypertension (16,17). TXAj synthesis has been... 

Brain TP receptors, shown to be present in both animal (37,38) and human (38,39) hrain tissues, were found to mediate calcium mobilization (38) and a hypertensive response in rats that was partially attributed to the release of arginine vasopressin (40). 

TP receptors were fotmd to be highly expressed on thymocytes (41,42), and TP receptor agonists stimulated apotosis of these cells (42). Since phagocytic cells of the thymic reticulum produced TXAj, along with PGEj and 6-keto-PGF, , and they were shown to regulate thymocyte proliferation in vitro (43), TXAj may exert a negative control on thymocyte proliferation. 

TP receptors are members of the broader class of prostanoid receptors that appear to constitute a sub mily within the ihodopsin-like, G protein-coupled receptor super mily (3). These G protein-coupled receptors (GPCR) have as a common stmctuial characteristic seven transmembrane alphajielices coimected by alternating extracellular and intracellular loops (44,45). Figure 1 illustrates the deduced amino acid sequence and the trans-membrane topology of the human TP receptor. 

Figure 1. Y= giycosylation sates Shaded circles=4iomology with mouse TP receptor. The sequence of the alternatively spliced endothelial-derived TP receptor (TP-P) carboxyl terminus is shown at the lower left. Figure (ref 242) reproduced with permission of Cayman Chemical, Arm Arbor, ML...

The human TP receptor gene is located on chromosome 19pl3.3 (61X die mouse gene is on chromosome 10 (62) and the rat gene is on chromosome 7ql 1 (63). 

TP receptor gene expression was stimulated by phorbol ester in human megadcaryoblastic leukemia (CHRF-288) cells (6S) and human ISL cells (66), but neither gluco-corticoids... 

Despite the description of several examples of impaired functional and biochemical responses to TP receptor agonists in human and animal platelets (70-76), only one TP receptor mutation has been described (77). A single amino acid substitution (R -L) was found in hxrman TXR-a cDNA obtained by RT-PCR from platelets of patients with a dominantly inherited bleeding disorder (See V. ALTERED TP RECEPTOR FUNCTION, A. TP RECEPTOR MUTATION below). 

Complete definition of the ligand binding domains of the TP receptor has not been accomplished as yet however, regions that appear to be important for ligand binding have been identified. Approachs to definition of these binding sites include the following ... 

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