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(Circulation Research. 1997;80:551-556.)
© 1997 American Heart Association, Inc.

Articles

Differential Desensitization of Thromboxane A₂ Receptor Subtypes

Masao Yukawa¹, Ryoji Yokota¹, Robert T. Eberhardt, Laila von Andrian, , J. Anthony Ware

From the Vascular Biology Unit, Cardiovascular Division, Beth Israel Hospital and Harvard Medical School, Boston, Mass.

Correspondence to J. Anthony Ware, MD, Cardiovascular Division, Albert Einstein College of Medicine, 1300 Morris Park Blvd, Bronx, NY 10461. E-mail jaware{at}aecom.yu.edu

Abstract Two subtypes of the thromboxane A₂ (TxA₂) receptor (TxA₂R-E and TxA₂R-P), which differ in their alternatively spliced cytoplasmic tails, have been identified. The initial concentration of the TxA₂ mimetic IBOP required to reduce peak intracellular Ca²⁺ concentration ([Ca²⁺]_i) induced by a second addition of IBOP (100 nmol/L) was similar (IC₅₀ for TxA₂R-E and TxA₂R-P, 0.46±0.16 and 0.40±0.07 nmol/L) in fibroblasts overexpressing either the TxA₂R-E or -P subtype. Although the number of TxA₂ binding sites decreased in TxA₂R-P cells after prolonged stimulation with a TxA₂ mimetic, those in the TxA₂R-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 TxA₂-induced [Ca²⁺]_i mobilization was measured. Forskolin reduced the IBOP-induced peak [Ca²⁺]_i in neither TxA₂R-E nor TxA₂R-P cells; however, treatment with phorbol esters (IC₅₀, 0.57±0.70 nmol/L) strongly prevented IBOP-mediated [Ca²⁺]_i rise in TxA₂R-E but not in TxA₂R-P cells. Desensitization of TxA₂R-E by phorbol esters was prevented by the PKC inhibitor calphostin C or by downregulation of PKC-. Thus, the response of TxA₂R-E to prolonged stimulation differs from that of TxA₂R-P in both the regulation of the number of binding sites and the mechanism for desensitization; agonists that activate PKC- might interfere with TxA₂R-E–mediated signaling.

Key Words: protein kinase C • prostaglandin • eicosanoid • desensitization • downregulation

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