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

Abstract

1. There has been considerable debate whether responses mediated via beta1- and beta2-adrenoceptors (beta1ARs and beta2ARs) display the same degree of desensitization after prolonged or repeated exposure to agonists. 2. Examples are provided for selective desensitization of functional responses and loss of binding sites for beta1ARs. Equally, examples are given of selective desensitization and down-regulation involving beta2ARs. 3. This review examines whether receptor subtype-selective desensitization of betaAR-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. 4. Methodological 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. 5. Four 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 betaARs 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 betaAR desensitization in the continued presence of agonist. Finally, the role of up-regulation of PDE in desensitization is discussed.

Cerebral oxygenation following epinephrine infusion

“…However, an overshoot in this recovery was evident 20 min post infusion, with a reduction in HR and Q, and an increase in TPR with respect to baseline. Combined, these data are consistent with a desensitization of β-adrenergic receptors following epinephrine infusion [25,26]. However, simultaneous with the post-infusion decreases in HR and Q (and increase in TPR) there was an increase in Oxy-Hb and Total-Hb, consistent with an increase in cortical perfusion and cerebral dilation.…”

Autonomic Nervous System Pharmacogenomics: A Progress Report

“…As discussed above, increases in catecholamines promote ␤-AR feedback regulation, i.e., desensitization and receptor down-regulation (Kohout and Lefkowitz, 2003). The ␤-AR subtypes differ in the extent to which they undergo such regulation with ␤ 2 -AR being the most susceptible (Suzuki et al, 1992;Zhou et al, 1995;Rousseau et al, 1996;Summers et al, 1997;Broadley, 1999).…”

Beyond the dogma: novel β2-adrenoceptor signalling in the airways

“…Despite improved asthma treatment options, adverse effects are not reported infrequently and increased numbers of asthma-related deaths associated with high-level use of certain agonists are well documented [7]. Although these adverse clinical events may be due to receptor or even whole pathway desensitisation [8], studies since the late 1990s suggest that promiscuous coupling of the b 2 -adrenoceptor to effectors other than the traditional cAMP/cAMP-dependent protein kinase (PK)A cascade may also be involved [9]. More fundamentally, the molecular mechanisms by which b 2 -adrenoceptor agonists cause ASM to relax are still not completely defined.…”