Multiple neurological abnormalities in mice deficient in the G protein G _o

Abstract

The G protein G o is highly expressed in neurons and mediates effects of a group of rhodopsin-like receptors that includes the opioid, ␣ 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. G o is an ␣␤␥ heterotrimeric G protein discovered in 1984 in brain by Neer and collaborators (1, 2) and by Sternweis and Robishaw (3), who all characterized it as a substrate for the ADP-ribosyltransferase activity of pertussis toxin. G o has received special attention for the following reasons: (i) It is the most abundant G protein in neurons, where it can constitute up to 2% of membrane protein (3). (ii) In addition to neurons, it appears to be expressed only on endocrine cells and heart, albeit at much lower levels comparable to those of the other heterotrimeric G proteins. (iii) G o is activated not only by the same class of seven-transmembrane receptors that activate the inhibitory G proteins G i1 -G i3 (4-9) but also by at least two proteins that do not belong to the rhodopsin-like family of G protein-coupled receptors, GAP43, an intracellular growth cone-associated protein active in neurite outgrowth (10), and the Alzheimer amyloid protein precursor protein responsible for familial forms of this disease (11). (iv) Except for inhibition of neuronal Ca 2ϩ channels, for which the mechanism of action of G o has been elucidated at the molecular level and shown to be due to the interaction of its ␤␥ moiety with the ␣ 1 subunit of the channel (6, 12-16), the mode of action of G o is essentially unknown. Tests for an ␣ i -like function for ␣ o have failed (17,18). Activated ␣ o has transformed NIH-3T3 cells (19) and activated mitogen-activated protein kinase activity in Chinese hamster ovary cells (20), phospholipase C in Xenopus oocytes, and K ϩ channels in neurons (21, 22), but how these effects come about has not been established. In fact, there is scant knowledge of the gamut of effector systems that may be the target(s) of activated G o .Gene ablation in mice is a powerful yet technically complex approach to identify as yet unknown functions of proteins that become manifest in mutated animals and͞or in cell lines derived from them. It has been applied to several G proteins with the following interesting results. G i2 -deficient mice were found to develop ulcerative colitis and adenocarcinomas, revealing an unexpected and as yet unexplained role of G i2 in the development of a chronic inflammatory response and very likely in lymphocyte homing to enteric epithelia (23, 24). Ablation of G q revealed an essential role for this G protein in platelet activation, because G q -deficient mice bleed and their platelets fail to be activated by physiologic activators such as collagen, thrombin, thromboxane, and ADP (25). Also the ablation of G o has been reported (26). Live mice, homozygous for loss of ␣ o , were obtained showing that...

Antihistamine antinociception is mediated by Gi-protein activation

“…The administration of PTX produced hyperalgesia and allodynia in laboratory animals (Ohnishi et al, 1990;Galeotti et al, 1996;Womer et al, 1997). A reduction of pain perception has also been observed in knock-out mice lacking for the gene encoding the subtype Go of the Gi-protein family (Jiang et al, 1998). These data clearly indicate that a lack of functionality of Gi-proteins enhances the sensitivity to pain.…”

G o 2 G protein mediates galanin inhibitory effects on insulin release from pancreatic β cells

“…This suggests that G o 2 is the major transducer mediating inhibitory effects on insulin release that prevent oversecretion. In this study, using G i / G o α-subunit gene knockout animals established in our laboratory (26,27), we demonstrate that the G o 2 G protein mediates galanin's inhibitory effect on insulin release. We also identify potentiation of ATP-sensitive potassium (K ATP ) currents and inhibition of Ca 2+ channels as possible molecular mechanisms mediating galanin-GalR-G o 2 signaling.…”

Exogenous nerve growth factor attenuates opioid-induced inhibition of voltage-activated Ba2+ currents in rat sensory neurons

“…G proteinmediated inhibition of VGCC involves interactions among three major proteins, namely the GPCR, the G protein, and the VGCC. In the case of the μ-opioid receptor, agonist binding causes activation of G proteins, primarily of the G o subtype (Moises et al, 1994;Jiang et al, 1998). The βγ subunits of the G protein heterotrimer dissociate from the α subunit and mediate inhibition of VGCC by direct binding to the α subunit of the VGCC (Herlitze et al, 1996;Ikeda, 1996;Zamponi et al, 1997;Delmas et al, 1998;Zamponi and Snutch, 1998).…”