Exposure of cells to agonists of receptors linked to G proteins can result in downregulation of cellular levels or redistribution of G proteins from membranes to the cytosol. Agonist-induced reductions in G protein levels have been observed for members of each of the G,, G; and G, families of G proteins, are likely to be dependent upon the level of receptor expression, and are generally restricted to the G protein (s) with which the receptor interacts. The mechanisms responsible, reviewed here by Graeme Milligan, vary with cell type and include both second messenger-dependent and-independent enhanced protein degradation. Agonist-induced reduction in cellular G protein levels can provide one mechanism for the development of sustained heter-ologous deiensitization. lated when cells are challenged by the maintained presence of an agonist3n4. In many situations, the G protein (s) that are activated by an agonist-occupied receptor are downregulated, while in some cases, a G protein that opposes the generation of the second mess-enger produced in response to the agonist is upregulated3*“. Regulation of cellular G protein levels can provide an appropriate locus to generate heterologous sensitization and desensitization4 and clearly contributes to the control of cellular sensitivity4. In many cases where G protein levels are regulated by agonists, the observations remain purely phenomenological, particularly in more physiologically relevant systems. However, in a certain range of cell

Maintained exposure of a cell to an agonist routinely results in sequestration and subsequent degradation of G protein-coupled receptors’ that recognize the particular agonist. Such processes are collectively termed downregulation and contribute to the battery of mechanisms, which constitute desensitization, by which a cell is able to limit either its sensitivity or maximal response to external stimuli*. Recently, it has become clear that receptors are not the only components of G proteinlinked cascades that can be regu-