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

• DOI: 10.1073/pnas.180194597
• Publication Date: 2002-07-26T14:31:44Z
• Authors: Jing Yang; Jie Wu; M. Anna Kowalska; Ashutosh Dalvi; Nicolas Prevost; Peter J. O'Brien; David Manning; Mortimer Poncz; Irwin Lucki; Julie A. Blendy; Lawrence F. Brass
• Keywords: Blood Platelets; Male; Mice, Knockout; Psychotropic Drugs; 0303 health sciences; Epinephrine; Morphine; Platelet Aggregation; Brain; Motor Activity; Platelet Activation; Heterotrimeric GTP-Binding Proteins; GTP-Binding Protein alpha Subunits; Mice; 03 medical and health sciences; Cocaine; Cyclic AMP; Animals; Humans; Collagen; Lung; Signal Transduction

Heterotrimeric G proteins mediate the earliest step in cell responses to external events by linking cell surface receptors to intracellular signaling pathways. Gzis a member of the Gifamily of G proteins that is prominently expressed in platelets and brain. Here, we show that deletion of the α subunit of Gzin mice: (i) impairs platelet aggregation by preventing the inhibition of cAMP formation normally seen at physiologic concentrations of epinephrine, and (ii) causes the mice to be more resistant to fatal thromboembolism. Loss of Gzαalso results in greatly exaggerated responses to cocaine, reduces the analgesic effects of morphine, and abolishes the effects of widely used antidepressant drugs that act as catecholamine reuptake inhibitors. These changes occur despite the presence of other Giαfamily members in the same cells and are not accompanied by detectable compensatory 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.