Reciprocal regulation of platelet responses to P2Y and thromboxane receptor activation

Background: Thromboxane A2 and ADP are two major platelet agonists that stimulate two sets of G protein‐coupled receptors to activate platelets. Although aggregation responses to ADP and thromboxane desensitize, there are no reports currently addressing whether activation by one agonist may heterologously desensitize responses to the other. Objectives: To demonstrate whether responses to ADP or U46619 may be modulated by prior treatment of platelets with the alternate agonist, revealing a level of cross‐desensitization between receptor systems. Results: Here we show that pretreatment of platelets with either agonist substantially desensitizes aggregation responses to the other agonist. Calcium responses to thromboxane receptor activation are desensitized by preactivation of P2Y1 but not P2Y12 receptors. This heterologous desensitization is mediated by a protein kinase C (PKC)‐independent mechanism. Reciprocally, calcium responses to ADP are desensitized by pretreatment of platelets with the thromboxane analogue, U46619, and P2Y12‐mediated inhibition of adenylate cyclase is also desensitized by pretreatment with U46619. In this direction, desensitization is comprised of two components, a true heterologous component that is PKC‐independent, and a homologous component that is mediated through stimulated release of dense granule ADP. Conclusions: This study reveals cross‐desensitization between ADP and thromboxane receptor signaling in human platelets. Cross‐desensitization is mediated by protein kinases, involving PKC‐dependent and independent pathways, and indicates that alterations in the activation state of one receptor may have effects upon the sensitivity of the other receptor system.