The G protein Go is highly expressed in neurons and mediates effects of a group of rhodopsin-like receptors that includes the opioid, alpha2-adrenergic, M2 muscarinic, and somatostatin receptors. In vitro, Go is also activated by growth cone-associated protein of Mr 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 Go may play in intact cells and whole body homeostasis, we disrupted the gene encoding the alpha subunits of Go in embryonic stem cells and derived Go-deficient mice. Mice with a disrupted alphao gene (alphao-/- mice) lived but had an average half-life of only about 7 weeks. No Goalpha was detectable in homogenates of alphao-/- 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 alphao-/- cells examined, the Ca2+ channel was activated at voltages that were 13.3 +/- 1.7 mV lower than in their counterparts. Loss of alphao was not accompanied by appearance of significant amounts of active free betagamma dimers (prepulse test). At the level of the living animal, Go-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, alphao-/- mice are hyperactive and exhibit a turning behavior that has them running in circles for hours on end, both in cages and in open-field tests. Except for one, all alphao-/- mice turned only counterclockwise. These findings indicate that Go plays a major role in motor control, in motor behavior, and in pain perception and also predict involvement of Go in Ca2+ channel regulation by an unknown mechanism.
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