J. Yang et al., Loss of signaling through the G protein, G(z), results in abnormal platelet activation and altered responses to psychoactive drugs, P NAS US, 97(18), 2000, pp. 9984-9989
Citations number
37
Categorie Soggetti
Multidisciplinary
Journal title
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
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.