Tools to study β3-adrenoceptors

Abstract

β 3 -adrenoceptors mediate some of the effects of catecholamines on tissues such as blood vessels or the urinary bladder and are putative targets for the treatment of diseases such as the overactive bladder syndrome. Progress in the understanding of the presence, function, and regulation of β 3 -adrenoceptors has been hampered by a lack of highly specific tools. "Classical" is not selective for β 3 -adrenoceptors, at least in humans, and may actually be a partial agonist. Radioligands, which are suitable either for the selective labeling of β 3 -adrenoceptors or for the nonselective labeling of all β-adrenoceptor subtypes, are also missing. β 3 -and β 1 /β 2 double knockout mice have been reported, but their usefulness for extrapolations in humans is questionable based upon major differences between humans and rodents with regard to the ligand recognition and expression profiles of β 3 -adrenoceptors. While the common availability of more selective agonists and antagonists at the β 3 -adrenoceptor is urgently awaited, the limitations of the currently available tools need to be considered in studies of β 3 -adrenoceptor for the time being.

Effects of β3-Adrenergic Receptor Activation on Rat Urinary Bladder Hyperactivity Induced by Ovariectomy

“…In addition, it is thought that the ␤ 3 AR is expressed endogenously at much lower levels in native tissues than in engineered cell lines. This evidence is based on radioligand binding assays, which use a high concentration of nonselective radiotracer, thus making it much more difficult to detect the ␤ 3 AR levels in native tissues versus the heterologous cell systems (Vrydag and Michel, 2007). Comparison of the staining patterns of the two antibodies in Fig.…”

“…␤ 3 ARs, which are considered the predominant subtype in human bladder, are coupled to excitatory G s and inhibitory G i proteins (Vrydag and Michel, 2007). Muscle relaxation is achieved via stimulation of G s , which increases cAMP.…”

Contrasts between the effects of zinc-α2-glycoprotein, a putative β3/2-adrenoceptor agonist and the β3/2-adrenoceptor agonist BRL35135 in C57Bl/6 (ob/ob) mice

“…Others and we regard this difference in potency as sufficient to describe BRL37344 as a 'selective' b 3 -adrenoceptor agonist, a term that should not be confused with 'specific' (Mencher & Wang 2005). It has been argued that BRL37344 is of limited value as a pharmacological tool because it is a muscarinic and a 1 -adrenoceptor antagonist (Vrydag & Michel 2007). Its potency at these receptors is, however, 1000-to 10 000-fold lower than its potency (pEC 50 Z8.7) as a stimulant of b 3 -adrenoceptor-mediated lipolysis in rat white and brown adipocytes , Hollenga et al 1990, Kubota et al 2002, Brahmadevara et al 2004, Briones et al 2005, Leblais et al 2005.…”

Pharmacogenomics of G Protein-Coupled Receptor Ligands in Cardiovascular Medicine

“…Among polymorphisms in the ␤ 3 -AR gene (ADRB3), only the W64R variant has been investigated in greater detail, predominantly in the context of metabolic regulation (Arch, 2008). Hence, little information is available addressing the potential effects of this SNP on drug responses in the cardiovascular system, at least partly reflecting the general paucity of data with ␤ 3 -selective ligands, which have been investigated in humans (Vrydag and Michel, 2007). Therefore, the following will focus on the pharmacogenomics of human ␤ 1 -and ␤ 2 -ARs.…”