Multiple neurological abnormalities in mice deficient in the G protein Go

被引:178
作者
Jiang, MS
Gold, MS
Boulay, G
Spicher, K
Peyton, M
Brabet, P
Srinivasan, Y
Rudolph, U
Ellison, G
Birnbaumer, L
机构
[1] Univ Calif Los Angeles, Sch Med, Dept Anesthesiol, Los Angeles, CA 90095 USA
[2] Univ Calif Los Angeles, Dept Biol Chem, Los Angeles, CA 90095 USA
[3] Univ Calif Los Angeles, Dept Mol Cell & Dev Biol, Los Angeles, CA 90095 USA
[4] Univ Calif Los Angeles, Dept Psychol, Los Angeles, CA 90095 USA
[5] Univ Calif Los Angeles, Brain Res Inst, Los Angeles, CA 90095 USA
[6] Univ Calif Los Angeles, Inst Mol Biol, Los Angeles, CA 90095 USA
[7] Baylor Coll Med, Dept Cell Biol, Houston, TX 77030 USA
关键词
D O I
10.1073/pnas.95.6.3269
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
The G protein G(o) is highly expressed in neurons and mediates effects of a group of rhodopsin-like receptors that includes the opioid, alpha(2)-adrenergic, M2 muscarinic, and somatostatin receptors. In vitro, G(o) is also activated by growth cone-associated protein of M-r 43,000 (GAP43) and the Alzheimer amyloid precursor protein, but it is not known whether this occurs in intact cells. To learn about the roles that G(o) may play in intact cells and whole body homeostasis, we disrupted the gene encoding the alpha subunits of G(o) in embryonic stem cells and derived G(o)-deficient mice. Mice with a disrupted alpha(o) gene (alpha(o)(-/-) mice) lived but had an average half-life of only about 7 weeks. No G(o) alpha was detectable in homogenates of alpha(o)(-/-) mice by ADP-ribosylation with pertussis toxin, At the cellular level, inhibition of cardiac adenylyl cyclase by carbachol (50-55% at saturation) was unaffected, but inhibition of Ca2+ channel currents by opioid receptor agonist in dorsal root ganglion cells was decreased by 30%, and in 25% of the alpha(o)(-/-) cells examined, the Ca2+ channel was activated at voltages that were 13.3 +/- 1.7 mV lower than in their counterparts, Loss of alpha(o) was not accompanied by appearance of significant amounts of active free beta gamma dimers (prepulse test), At the level of the living animal, G(o)-deficient mice are hyperalgesic (hot-plate test) and display a severe motor control impairment (falling from rotarods and 1-inch wide beams). In spite of this deficiency, alpha(o)(-/-) mice are hyperactive and exhibit a turning behavior that has them running in circles for hours on end, bath in cages and in open-field tests. Except for one, all alpha(o)(-/-) mice turned only counterclockwise. These findings indicate that G(o) plays a major role in motor control, in motor behavior, and in pain perception and also predict involvement of G(o) in Ca2+ channel regulation by an unknown mechanism.
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页码:3269 / 3274
页数:6
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