The Odd Sibling: Features ofβ₃-Adrenoceptor Pharmacology

Abstract

b 3 -Adrenoceptor agonists have recently been introduced for the treatment of overactive urinary bladder syndrome. Their target, the b 3 -adrenoceptor, was discovered much later than b 1 -and b 2 -adrenoceptors and exhibits unique properties which make extrapolation of findings from the other two subtypes difficult and the b 3 -adrenoceptor a less-understood subtype. This article discusses three aspects of b 3 -adrenoceptor pharmacology. First, the ligand-recognition profile of b 3 -adrenoceptors differs considerably from that of the other two subtypes, i.e., many antagonists considered as nonselective actually are b 3 -sparing, including propranolol or nadolol. Many agonists and antagonists classically considered as being b 3 -selective actually are not, including BRL 37,344 ( (6) . Moreover, the binding pocket apparently differs between the human and rodent b 3 -adrenoceptor, yielding considerable species differences in potency. Second, the expression pattern of b 3 -adrenoceptors is more restricted than that of other subtypes, particularly in humans; this makes extrapolation of rodent findings to the human situation difficult, but it may result in a smaller potential for side effects. The role of b 3 -adrenoceptor gene polymorphisms has insufficiently been explored and may differ even between primate species. Third, b 3 -adrenoceptors lack the phosphorylation sites involved in agonist-induced desensitization of the other two subtypes. Thus, they exhibit downregulation and/or desensitization in some, but not other, cell types and tissues. When desensitization occurs, it most often is at the level of mRNA or signaling molecule expression. All three of these factors have implications for future studies to better understand the b 3 -adrenoceptor as a novel pharmacological target.

Role of host β1- and β2-adrenergic receptors in a murine model of B16 melanoma: functional involvement of β3-adrenergic receptors

“…2f). To evaluate whether β3-AR upregulation is specifically restricted to tumor tissues or β1/2-AR deletion may affect β3-AR levels in tissues of the host known to express some quantifiable amount of β3-ARs in the WT (Cernecka et al 2014b;Dal Monte et al 2015), we evaluated protein levels of β3-AR in brown adipose tissue, gall bladder, heart, brain, and retina of both WT and β1/2-AR KO. As shown in Online Resource 3, levels of β3-ARs did not differ between WT and β1/2-AR KO in brown adipose tissue, gall bladder, brain, and retina, while they were increased by 163 % (P < 0.01) in the heart of β1/2-AR KO.…”

Mirabegron causes relaxation of human and rat corpus cavernosum: could it be a potential therapy for erectile dysfunction?

“…However, the difference between mirabegron and BRL 37344 for methylene blue-induced inhibition is unclear at present. Similar distinct effects have long existed for b 3 -adrenoceptor agonists [34]. Besides many b 3 -adrenoceptor ligands exhibit species differences in affinity to these agonists.…”

β-Adrenoceptor-Mediated Relaxation of Carbachol-Pre-Contracted Mouse Detrusor

“…2d), also suggesting minor involvement of other β-AR subtype. Since pharmacological identification of β-AR subtypes heavily depends on the properties of putatively selective antagonists, which is not necessarily always the case [24]. We have also used β 2 -AR-KO mice to confirm the dominant role of this β 2 -AR subtype in CCh-precontracted muscles.…”