Loss of signaling through the G protein, Gz, results in abnormal platelet activation and altered responses to psychoactive drugs.
Heterotrimeric G proteins mediate the earliest step in cell responses to external 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 prominently expressed in platelets and brain. Here, we show that deletion of the alpha subunit of G(z) in 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 G(zalpha) also 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 G(ialpha) family 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.
Yang
J
J
Departments of Medicine, Pediatrics, Psychiatry, and Pharmacology, University of Pennsylvania School of Medicine, 421 Curie Boulevard, Philadelphia, PA 19104, USA.
Wu
J
J
Kowalska
M A
MA
Dalvi
A
A
Prevost
N
N
O'Brien
P J
PJ
Manning
D
D
Poncz
M
M
Lucki
I
I
Blendy
J A
JA
Brass
L F
LF
D000818:Animals; D001792:Blood Platelets / Q000187:drug effects / Q000502:physiology*; D001921:Brain / Q000187:drug effects / Q000502:physiology*; D003042:Cocaine / Q000494:pharmacology; D003094:Collagen / Q000494:pharmacology; D000242:Cyclic AMP / Q000097:blood; D004837:Epinephrine / Q000494:pharmacology; D044385:GTP-Binding Protein alpha Subunits; D020962:Heterotrimeric GTP-Binding Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D008168:Lung / Q000187:drug effects / Q000503:physiopathology; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009020:Morphine / Q000494:pharmacology; D009043:Motor Activity; D015539:Platelet Activation / Q000502:physiology*; D010974:Platelet Aggregation; D011619:Psychotropic Drugs / Q000494:pharmacology*; D015398:Signal Transduction; D013923:Thromboembolism / Q000235:genetics / Q000503:physiopathology / Q000517:prevention & control
C099387:GNAZ protein, human; D044385:GTP-Binding Protein alpha Subunits; C490964:Gnaz protein, mouse; D011619:Psychotropic Drugs; D009020:Morphine; D003094:Collagen; D000242:Cyclic AMP; D020962:Heterotrimeric GTP-Binding Proteins; D003042:Cocaine; D004837:Epinephrine