Differential desensitization of thromboxane A2 receptor subtypes

Yukawa, M.; Yokota, R.; Eberhardt, R.T.; von Andrian, L.; Ware, J.A.

Circulation Research 80(4): 551-556

1997


ISSN/ISBN: 0009-7330
PMID: 9118486
Accession: 008469910

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Abstract
Two subtypes of the thromboxane A-2 (TxA-2) receptor (TxA2R-E and TxA-2R-P), which differ in their alternatively spliced cytoplasmic tails, have been identified. The initial concentration of the TxA-2 mimetic IBOP required to reduce peak intracellular Ca-2+ Concentration ((Ca-2+)-1)induced by a second addition of IBOP (100 nmol/L) was similar (IC-50 for TxA-2R-E and TxA-2R-P, 0.46-0.16 and 0.40+-0.07 nmol/L) in fibroblasts overexpressing either the TXA-2R-E or -P subtype. Although the number of TxA-2 binding sites decreased in TXA-2R-P cells after prolonged stimulation with a TxA-2 mimetic, those in the TXA-2R-E cells increased markedly. To determine whether the mechanism for desensitization differs between subtypes, the effect of activation of protein kinase C (PKC) or cAMP-dependent kinase on TxA-2-induced (Ca-2+)-i mobilization was measured. Forskolin reduced the IBOP-induced peak (Ca-2+)-i in neither TXA-2-E nor TxA-2R-P cells; however, treatment with phorbol esters (IC-50, 0.57+-0.70 nmol/L) strongly prevented IBOP-mediated (Ca-2+)-i rise in TxA-2R-E but not in TXA-2R-P cells. Desensitization of TxA2R-E by phorbol esters was prevented by the PKC inhibitor calphostin C or by downregulation of PKC-alpha. Thus, the response of TxA-2R-E to prolonged stimulation differs from that of TXA-2R-P in both the regulation of the number of binding sites and the mechanism for desensitization; agonists that activate PKC-alpha might interfere with TxA-2R-E-mediated signaling.