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

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

Everything You Always Wanted to Know about β3-AR * (* But Were Afraid to Ask)

“…The N-terminal region of β 3 -AR is extracellular and glycosylated, whereas the C-terminus is intracellular. Unlike in β 1 - and β 2 -AR, it lacks sites for phosphorylation by protein kinase A (PKA) and β-adrenoceptor kinase (βARK) thereby making β 3 -AR relatively resistant to desensitization [17,22,23]. Among others, this feature contributed in making β 3 -AR an interesting therapeutic target that would potentially be suitable for chronic treatments.…”

“…Among others, this feature contributed in making β 3 -AR an interesting therapeutic target that would potentially be suitable for chronic treatments. From a molecular point of view, desensitization of β 3 -AR might not be mediated by internalization/degradation of the receptor, as for β 1 -AR [24], but rather by downregulation of downstream components of the signaling pathway [25] or even mRNA regulation (reviewed in [23]). However, caution must be used when evaluating the data present in literature as results were not always consistent (reviewed in [23]).…”

“…From a molecular point of view, desensitization of β 3 -AR might not be mediated by internalization/degradation of the receptor, as for β 1 -AR [24], but rather by downregulation of downstream components of the signaling pathway [25] or even mRNA regulation (reviewed in [23]). However, caution must be used when evaluating the data present in literature as results were not always consistent (reviewed in [23]). Transmembrane domains TM3, TM4, TM5, and TM6 are essential for ligand binding, whereas TM2 and TM7 are involved in Gαs activation [26].…”

β3‐Adrenoceptors in the normal and diseased urinary bladder—What are the open questions?

“…Many investigators have studied agonist‐induced desensitization of β 3 ‐adrenoceptors in a wide range of animal tissues and of the human subtypes upon endogenous expression and transfection in various cell lines, as reviewed in detail elsewhere in this issue (Okeke, Angers, Bouvier, & Michael, ). While there is consensus that β 3 ‐adrenoceptors are less sensitive to agonist‐induced desensitization as compared to β 1 ‐ and β 2 ‐adrenoceptors, whether they exhibit agonist‐induced desensitization and which mechanisms are involved appears to be highly cell type‐dependent.…”

Where will the next generation of medical treatments for overactive bladder syndrome come from?

“…29,30 One explanation for this might be the potential of agonists to cause desensitization. Although b 3 -adrenoceptors were originally believed to be resistant to agonist-induced desensitization, it is now clear that these receptors at least in some tissues and cell types can undergo desensitization; 31 whether this also applies to the human bladder in vivo remains unclear. Similar to muscarinic antagonists, the efficacy of mirabegron relative to placebo was only moderate in controlled studies, 16 but considerably larger in a non-interventional study.…”