Desensitization of the P2Y¹ receptor in platelets

Abstract

Understanding thrombosis is critical for effective treatment of patients at risk for heart attack and stroke. Simultaneous activation of the Gq‐coupled P2Y1 receptor and the Gi‐coupled P2Y12 receptor is required for ADP‐promoted platelet aggregation— deletion or inhibition of either receptor results in the loss of ADP‐induced aggregation. Unlike the P2Y12 receptor, the P2Y1 receptor in both mouse and human platelets undergoes profound and rapid desensitization in response to sub‐aggregating levels of ADP. We hypothesize that this rapid inactivation is specific to the P2Y1 receptor and is physiologically relevant for proper regulation of platelet hemostasis. To test the specificity of desensitization, we compared the rate of desensitization after agonist addition of the 5HT2A and TxA2 receptors, which are also Gq‐coupled, to that of the P2Y1 receptor. These data reveal that only the P2Y1 receptor rapidly desensitizes in response to its cognate agonist. To determine the residue(s) responsible for P2Y1 desensitization, we transplanted retrovirally infected bone marrow cells expressing P2Y1 receptor Ser/Thr mutants into P2Y1−/− mice to examine the desensitization of the P2Y1 receptor ex vivo. These mice will also be used to examine the physiological consequences of expressing a non‐desensitizing P2Y1 receptor by measuring thrombus formation in vivo in response to arterial vessel wall injury.(Supported by NIH grant HL54889)