2 THROMBOXANE A(2) RECEPTOR ISOFORMS IN HUMAN PLATELETS - OPPOSITE COUPLING TO ADENYLYL-CYCLASE WITH DIFFERENT SENSITIVITY TO ARG(60) TO LEU MUTATION

Thromboxane A(2) (TXA(2)) receptor is a key molecule in hemostasis as its abnormality leads to bleeding disorders. Two isoforms of the human TXA(2) receptor have been cloned; one from placenta and the other fro m endothelium, here referred to as TXR alpha and TXR beta, respectivel y. These isoforms differ only in their carboxyl-terminal tails. We rep ort that both isoforms are present in human platelets. The two isoform s expressed in cultured cells show similar ligand binding characterist ics and phospholipase C (PLC) activation but oppositely regulate adeny lyl cyclase activity; TXR alpha activates adenylyl cyclase, while TXR beta inhibits it. The Arg(60) to Leu mutant of TXR alpha, which has be en shown to impair PLC activation (Hirata, T., A. Kakizuka, F. Ushikub i, I. Fuse, M. Okuma, and S. Narumiya. 1994. J. Clin. Invest. 94: 1662 -1667), also impairs adenylyl cyclase stimulation, whereas that of TXR beta retains its activity to inhibit adenylyl cyclase. These findings suggest that the pathway linked to adenylyl cyclase inhibition might be involved in some of the TXA(2)-induced platelet responses such as s hape change and phospholipase A(2) activation which remain unaffected in the patients with this mutation.