Maintaining cell sensitivity to G-protein coupled receptor agonists: neurotensin and the role of receptor gene activation.

In the last few years, a number of studies have brought new insights into the fundamental mechanisms of cell desensitization and internalization of G-protein coupled receptors. Such studies have demonstrated that cells remain desensitized from a few minutes to several hours, after exposure to high concentrations of agonist. However, in vivo, agonists such as hormones are always present, even in small amounts, and such long desensitization is not conceivable, since constant stimulation of cells is required for physiological responses. Under such circumstances, cells would require a means to permanently maintain sensitivity to various internal or external stimuli. In the present review, we have taken as an example the expression of the high affinity neurotensin receptor, a seven transmembrane G-protein coupled receptor, upon prolonged exposure to its agonist, and observed that cells remained sensitive only if the receptor gene was activated by the agonist. Consequently, new receptors were synthesized, and either delivered to the cell surface or accumulated in submembrane pools. This regulation takes place only after prolonged and intense agonist stimulation. Under these conditions, it is proposed that receptor turnover is accelerated in proportion to the agonist concentration in order to allow the cells to produce an adapted cellular response to external stimuli. Such mechanisms thus play a key role in cell sensitivity to hormones.