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

Received: 19 September 2018 Revised: 27 January 2019 Accepted: 11 February 2019 DOI: 10.1111/bph.14633 Themed Section: Adrenoceptors—New Roles for Old Players BJP REVIEW ARTICLE Agonist‐induced desensitisation of β3‐adrenoceptors: Where, when, and how? Katerina Okeke1 | Stephane Angers2 | Michel Bouvier3 | Martin C. Michel1 1 Department of Pharmacology, Johannes Gutenberg University, Mainz, Germany 2 Leslie Dan Faculty of Pharmacy and Department of Biochemistry, University of Toronto, Toronto, ON, Canada 3 Institute for Research in Immunology and Cancer, Department of Biochemistry and Molecular Medicine, Université de Montréal, Montréal, QC, Canada Correspondence Martin C. Michel, Department of Pharmacology, Johannes Gutenberg University, Obere Zahlbacher Str. 67, 55131 Mainz, Germany. Email: marmiche@uni‐mainz.de Funding information Velicept; Astellas; Deutsche Forschungsgemeinschaft, Grant/Award Number: Mi 294/8‐1 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 1 | I N T RO D U CT I O N (Nergardh, Boreus, & Naglo, 1977), which looked to be mediated by β‐adrenoceptors based on the order of potency of catecholamines. In 1967, Lands, Arnold, McAuliff, Luduena, and Brown (1967) proposed However, the existence of a third subtype, the β3‐adrenoceptor, only a subdivision of β‐adrenoceptors into β1 and β2. Soon thereafter, it became fully accepted after it was cloned in 1989 (Emorine et al., emerged that some β‐adrenergic‐like responses were not mediated by 1989). β3‐adrenoceptors have a more restricted expression pattern in either of these two subtypes (Furchgott, 1972). This included lipolytic humans than β1‐ or β2‐adrenoceptors (Michel & Gravas, 2016) and have responses in rat white adipose tissue (Harms, Zaagsma, & van a unique and species‐dependent ligand recognition profile, including a der Wal, 1974) and smooth muscle relaxation responses in rat low affinity for propranolol and several other classic antagonists colon (Bianchetti & Manara, 1990) and human urinary bladder previously considered to block all β‐adrenoceptor subtypes (Cernecka, Br J Pharmacol. 2019;176:2539–2558. wileyonlinelibrary.com/journal/bph © 2019 The British Pharmacological Society 2539 2540 OKEKE ET AL. BJP Sand, & Michel, 2014). Some agonists including mirabegron confirmed for many other GPCRs, the relative roles of the contribut- and solabegron have higher affinity for the human than the rodent ing β3‐adrenoceptor, whereas others including BRL 27,344 and ritobegron tisation differ among GPCRs. Even closely related receptors such have higher affinity for the rodent receptor. Similarly, some agonists as β2‐ and β1‐adrenoceptors may exhibit differential regulation including CL 316,243 have greater efficacy at the rodent than the (Marullo, Nantel, Strosberg, & Bouvier, 1995; Michel, Feth, human receptor (Baker, 2005). While β3‐adrenoceptors play a key role Sundermann, Rascher, & Brodde, 1993). mechanisms as well as the time courses of desensi- in lipolysis in rodents, particularly in brown adipose tissue, brown adi- Based on the relative lack of phosphorylation sites in its C‐terminus pose tissue is largely lacking in adult humans, and lipolysis in white adi- (Emorine et al., 1989; Lelias et al., 1993; Muzzin et al., 1991; pose tissue involves β3‐adrenoceptor only to a minor extent, if at all, in Nahmias et al., 1991), it was originally assumed that β3‐adrenoceptors humans (Lönnqvist et al., 1993). Finally, the mouse β3‐adrenoceptor are gene has splice variants, whereas the human orthologue does not assumption was supported by some early studies (Granneman, 1992; (Evans, Papaioannou, Hamilton, & Summers, 1999). Nantel et al., 1993), later work shows that desensitisation can occur resistant to agonist‐induced desensitisation. While this Recently, β3‐adrenoceptor agonists have been introduced clinically in at least some settings (Nantel, Bouvier, Strosberg, & Marullo, for the treatment of the overactive bladder syndrome. While they 1995). Therefore, this review will concentrate on tissues and cell types effectively improve bladder symptoms and are well tolerated (Chapple, in which β3‐adrenoceptor desensitisation occurs upon prolonged Cardozo, Nitti, Siddiqui, & Michel, 2014; Ohlstein, von Keitz, & Michel, agonist exposure, and what possibly differentiates these from those 2012; Yoshida, Takeda, Gotoh, Nagai, & Kurose, 2018), they are not where desensitization does not occur. We will discuss desensitisation curative, implying a need for long‐term treatment. Other β‐ of tissue and cell responses, including those of signal transduction, adrenoceptor subtypes exhibit desensitisation upon extended expo- and the underlying molecular and cellular mechanisms. We will also sure to an agonist, for instance, in the use of β2‐adrenoceptor agonists discuss the implications of β3‐adrenoceptor desensitisation for for treatment of preterm labour (Engelhardt et al., 1997; Frambach chronic treatment with corresponding agonists. Of note, some et al., 2005; Michel, Pingsmann, Nohlen, Siekmann, & Brodde, 1989). studies reporting on desensitisation of responses apparently occurring This can limit the effectiveness of this treatment for women with pre- via β3‐adrenoce (...truncated)