Loss of signaling through the G protein, G(z), results in abnormal platelet activation and altered responses to psychoactive drugs

Heterotrimeric G proteins mediate the earliest step in cell responses to ex ternal events by linking cell surface receptors to intracellular signaling pathways. G(z) is a member of the G(i) family of G proteins that is promine ntly expressed in platelets and brain. Here, we show that deletion of the a subunit of G(z) in mice: (i) impairs platelet aggregation by preventing th e inhibition of cAMP formation normally seen at physiologic concentrations of epinephrine, and (ii) causes the mice to be more resistant to fatal thro mboembolism. Loss of G(z alpha) also results in greatly exaggerated respons es to cocaine, reduces the analgesic effects of morphine, and abolishes the effects of widely used antidepressant drugs that act as catecholamine reup take inhibitors. These changes occur despite the presence of other G(i alph a) family members in the same cells and are not accompanied by detectable c ompensatory changes in the level of expression of other G protein subunits. Therefore, these results provide insights into receptor selectivity among G proteins and a model for understanding platelet function and the effects of psychoactive drugs.