TURNING OFF THE SIGNAL - DESENSITIZATION OF BETA-ADRENERGIC-RECEPTOR FUNCTION

Cellular responses to many hormones and neurotransmitters wane rapidly despite continuous exposure of cells to these stimuli. This phenomenon, termed desensitization, has been particularly well studied for the stimulation of cAMP levels by plasma membrane β-adrenergic receptors (βAR). The molecular mechanisms underlying rapid βAR desensitization do not appear to require internalization of the receptors, but rather an alteration in the functioning of βAR themselves that uncouples the receptors from the stimulatory G protein G(s). This uncoupling phenomenon involves phosphorylation of βAR by at least two kinases, PKA and the βAR kinase (βARK), which are activated under different desensitizing conditions. Receptor phosphorylation by the two kinases leads to desensitization of the receptor response via distinct biochemical mechanisms, and additional cytosolic factors appear to be involved in the case of βARK. Numerous experimental approaches have been used recently to elucidate the molecular details of this ubiquitous biological process.