Review of mechanisms involved in the apparent differential desensitization of β1‐ and β2‐adrenoceptor‐mediated functional responses

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Abstract
Summary: 1There has been considerable debate whether responses mediated via β1‐ and β2‐adrenoceptors (β1ARs and β2ARs) display the same degree of desensitization after prolonged or repeated exposure to agonists.2Examples are provided for selective desensitization of functional responses and loss of binding sites for β1ARs. Equally, examples are given of selective desensitization and down‐regulation involving β2ARs.3This review examines whether receptor subtype‐selective desensitization of βAR‐mediated responses can occur and whether even within the same subtype, there may be tissue‐selective desensitization. Possible reasons why apparent selectivity of desensitization of functional responses may occur are considered and are divided into methodological and non‐methodological factors.4Methodological factors discussed are: the concentration of agonist used for inducing desensitization and the washout times before construction of the post‐incubation concentration‐response curve (CRC), the need for correction of CRCs from time‐matched controls, and the methods adopted for plotting CRCs.5Four non‐methodological factors are considered. Firstly, the roles of different receptor reserves for the responses of each tissue can have an important effect on whether desensitization is apparent; a large reserve will make desensitization less likely to be apparent. Secondly, there is more than one site at which desensitization occurs; receptors are uncoupled from adenylyl cyclase activation, there is an additional site at the level of stimulation of cyclic AMP‐dependent protein kinase and βARs may ultimately be down‐regulated. These processes may differ depending on the tissue and conditions and this may influence whether differential desensitization occurs between tissues. Thirdly, the apparent degree of desensitization after washout of an agonist can depend upon the rate of resensitization. Experiments to overcome this problem are described which demonstrate βAR desensitization in the continued presence of agonist. Finally, the role of up‐regulation of PDE in desensitization is discussed.

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