Activation of G(i)-coupled receptors releases a tonic state of inhibited platelet aggregation

Single-receptor pharmacology does not satisfactorily explain the physiology of the ADP-induced platelet aggregation response. It has been shown that, in addition to G(q)-coupled receptor activation, one G(i)-coupled receptor, either the ADP P-2T or the alpha (2)-adrenoceptor, is required for elicita tion of aggregation. The underlying mechanism of this action, however, has not been elucidated, By systematically assaying the entire time course of t he aggregation and its fade using two methods of aggregometry, me have inve stigated the role of graded activation of these two Gi-coupled receptors, W e demonstrate that constant activation of either of two G(q)- coupled recep tors, the ADP P2Y(1) or the 5-HT2A, and incremental activation of either of the two G(i)-coupled receptors, tightly regulates the aggregation response in vitro, through the apparent release of a tonic inhibition of platelet a ggregation. This tightly regulated release of inhibition, which appears ana logous to the phenomena of disinhibition observed in the central nervous sy stem, may be instrumental for the continuous adaptation of the aggregation response to variable physiological conditions.