G proteins are involved in cellular signalling and regulate a variety of biological processes including differentiation and development. We have generated mice deficient for the G protein subunit alpha i2 (G alpha i2) by homologous recombination in embryonic stem cells. G alpha i2-deficient mice display growth retardation and develop a lethal diffuse colitis with clinical and histopathological features closely resembling ulcerative colitis in humans, including the development of adenocarcinoma of the colon. Prior to clinical symptoms, the mice show profound alterations in thymocyte maturation and function. The study of these animals should provide important insights into the pathogenesis of ulcerative colitis as well as carcinogenesis.

Antidiuresis, the recovery of water from the lumen of the renal collecting tubule, is regulated by the hypothalamic release of antidiuretic hormone (ADH), which binds to specific receptors on renal collecting tubule cells, stimulates adenylyl cyclase and promotes the cyclic AMP-mediated incorporation of water pores into the luminal surface of these cells. We report here the isolation of the human ADH receptor gene using a genomic expression cloning approach. The gene was used to clone the complementary DNA from a human renal library. The deduced amino-acid sequence of the receptor yields a hydropathy profile characteristic of receptors with seven putative transmembrane regions. This and the comparison with other cloned receptors indicates that the ADH receptor is a member of the superfamily of G-protein-coupled receptors.

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...