Altered TP Receptor Function

The one htunan TP receptor mutation (R -L), described by Hirata, et al (77) was manifested by defective signal transduction from receptors to PLC-P and a mild bleeding 

Other human subjects with defective TP receptor agonist-stimulated platelet aggre-gation have been described (70-73), but a specific signal transduction abnormality has been defined in only one individual (73). 

The cause of this defect was not deteimined, but a mutation in the TP gene was excluded. A defect in PLC-P or in Ga was postulated (72). Since the patient s platelets also demonstrated inq aiied aggregation m response to ADP it is possible that she d mild PLC-P deficiency, a defect found to be a cause of impaired platelet aggregation and secretion stimulated by multiple agonists (73). However, this is less likely since a normal response to thrombin was observed. 

Conpared to human platelets, the fimctional responses of animal platelets to TP receptor agonists are quite varied. Platelets fh)m some species, such as cats, guinea pigs and rabbits, were repotted to aggregate irreversibly when stirred with sodium arachidonate or 9,ll-azo-PGH2, while sheep and dog platelets feiled to aggregate under the same conditions (74,172). Horse platelets aggregated reversibly in response to arachidonate 

The biochemical basis for TXAj- dog platelets has been extensively studied and partially defined. Both TXAj- and TXAj+ dog platelets were found to bind TP receptor agonists and antagonists with equal affinity to a comparable number of high affinity (nM Kd) receptors in equilibrium binding assays however, agonist binding to TP receptors on TXAj- platelets resulted in markedly impaired GTPase and PLC-P activation compared 

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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). 

Endothelium-dependent pulmonary artery contractions in response to arachidonic acid or methacholine appeared to be mediated by TXAj in rabbits (179). However, approximately 25% of normal New Zealand White rabbits ftuled to demonstrate pulmonary artery contraction in response to arachidonic acid, U46619 or I-BOP. These "unresponsive" rabbits were found to have only 23% of the TP receptors present on pulmonary and aortic crade membranes of "responsive" rabbits (179). Of interest was the feet that platelets fix>m "unresponsive" rabbits aggregated as well or better than platelets firom "responsive" animals vdien stirred with U46619, and no deficiency ofTP receptors nor binding affinity was found. These data sug sted that TP receptor expression may be tissue tecific. This conclusion was supported by the observation that ir bition of testosterone 5a-reductase in tats decreased TP receptor density on aortic membranes but not on platelets (180) (See V. ALTERED TP RECEPTOR FUNCTION, 3. DRUG EFFECTS, a. HORMONES below). 

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