[Mechanisms of desensitization of beta-adrenergic receptors]

Desensitization of beta-adrenergic receptors means loss of receptor activity due to overstimulation by beta-mimetic drugs. Desensitization has been demonstrated in experimental studies using cell cultures, isolated organs and in vivo models. It generally evolves in two steps: uncoupling between the receptor and adenylate cyclase is followed by a decrease of the number (or down-regulation) of receptors. Desensitization can be either specific or non specific. In the first case, the phenomenon is related to the occupation of the receptor by an agonist and the occupied receptor only is altered (homologous desensitization). In the second case, the phenomenon is related to production in excess of cyclic AMP and other adenylate cyclase-coupled receptors are altered (heterologous desensitization). Studies performed on cellular models have shown that beta-receptor desensitization can be related to phosphorylation of the receptor by a cyclic AMP-dependent protein-kinase and that down-regulation corresponds to the incorporation of the beta-receptors in cytoplasmic vesicles. Desensitization has also been related to the activation of membrane phospholipid metabolism and the production of prostaglandins. Studies of bronchial beta-adrenergic receptors, mostly performed on isolated organs, have shown that beta-mimetic and, in some cases, phosphodiesterase inhibitor drugs can induce desensitization of beta-receptors. The possibility of beta-adrenergic receptor activity and desensitization independent of adenylate cyclase and cyclic AMP has also been evoked. In clinical practice, the reality of beta-adrenergic desensitization is still controversial. The existence of a variable proportion of "spare" receptors could explain the variability of patient responses to the long-term treatment of asthma by beta-mimetic drugs.