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Review
. 2019 Jul;176(14):2539-2558.
doi: 10.1111/bph.14633. Epub 2019 Apr 7.

Agonist-induced desensitisation of β3 -adrenoceptors: Where, when, and how?

Katerina Okeke  1 , Stephane Angers  2 , Michel Bouvier  3 , Martin C Michel  1
Affiliations
Review

Agonist-induced desensitisation of β3 -adrenoceptors: Where, when, and how?

Katerina Okeke et al. Br J Pharmacol. 2019 Jul.

Abstract

β3 -Adrenoceptor agonists have proven useful in the treatment of overactive bladder syndrome, but it is not known whether their efficacy during chronic administration may be limited by receptor-induced desensitisation. Whereas the β2 -adrenoceptor has phosphorylation sites that are important for desensitisation, the β3 -adrenoceptor lacks these; therefore, it had been assumed that β3 -adrenoceptors are largely resistant to agonist-induced desensitisation. While all direct comparative studies demonstrate that β3 -adrenoceptors are less susceptible to desensitisation than β2 -adrenoceptors, desensitisation of β3 -adrenoceptors has been observed in many models and treatment settings. Chimeric β2 - and β3 -adrenoceptors have demonstrated that the C-terminal tail of the receptor plays an important role in the relative resistance to desensitisation but is not the only relevant factor. While the evidence from some models, such as transfected CHO cells, is inconsistent, it appears that desensitisation is observed more often after long-term (hours to days) than short-term (minutes to hours) agonist exposure. When it occurs, desensitisation of β3 -adrenoceptors can involve multiple levels including down-regulation of its mRNA and the receptor protein and alterations in post-receptor signalling events. The relative contributions of these mechanistic factors apparently depend on the cell type under investigation. Which if any of these factors is applicable to the human urinary bladder remains to be determined. LINKED ARTICLES: This article is part of a themed section on Adrenoceptors-New Roles for Old Players. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v176.14/issuetoc.

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Conflict of interest statement

M.C.M. is a consultant to Astellas and a consultant and shareholder of Velicept.

Figures

Figure 1
Figure 1
Desensitisation of cAMP accumulation mediated by human β3‐adrenoceptors transfected into CHO and HEK 293 cells. Cells were treated for 24 hr with 10 μM isoprenaline or vehicle, followed by washout and exposure to fresh isoprenaline. Desensitisation was observed in HEK 293 but not in CHO cells. Reproduced with permission from Michel‐Reher and Michel (2013)
Figure 2
Figure 2
Time course of agonist‐promoted internalisation of the β3‐, β2‐, and a β3‐3232 chimeric adrenoceptor. HEK 293 cells stably expressing the β2‐adrenoceptor, β3‐adrenoceptor, or the β3‐3232 (chimeric) were stimulated with 100 μM isoprenaline for the indicated times. Each of the constructs was tagged at their N‐terminus with a Myc‐tag allowing their immuno‐detection using an anti‐Myc antibody. Internalisation was assessed by flow cytometry and expressed as % loss of cell surface receptor immunoreactivity. Reproduced with permission from Angers (2003). The data show that in contrast to the β2‐adrenoceptor that undergoes a time‐dependent internalisation upon isoprenaline stimulation, the β3‐adrenoceptor does not. However, introducing the second intracellular loop and the carboxyl‐terminus of the β2‐adrenoceptor within the β3‐adrenoceptor backbone (β3‐3232) restored agonist‐promoted internalisation to some extent
Figure 3
Figure 3
Schematic diagram of key aspects of β3‐adrenoceptor function and regulation. In many if not most tissues and cell types, these do not change upon prolonged agonist exposures, but in some, each of them may decrease (except for Gi, which may increase). For details, see main text
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