Tissue functions mediated by β3-adrenoceptors—findings and challenges

Archiv für Experimentelle Pathologie und Pharmakologie (Impact Factor: 2.36). 08/2010; 382(2):103-8. DOI: 10.1007/s00210-010-0529-2
Source: PubMed

ABSTRACT As β3-adrenoceptor agonists metamorphose from experimental tools into therapeutic drugs, it is vital to obtain a comprehensive
picture of the cell and tissue functions mediated by this receptor subtype in humans. Human tissues with proven functions
and/or a high expression of β3-adrenoceptors include the urinary bladder, the gall bladder, and other parts of the gastrointestinal tract. While several
other β3-adrenoceptor functions have been proposed based on results obtained in animals, their relevance to humans remains uncertain.
For instance, β3-adrenoceptors perform an important role in thermogenesis and lipolysis in rodent brown and white adipose tissue, respectively,
but their role in humans appears less significant. Moreover, the use of tools such as the agonist BRL 37344 and the antagonist
SR59230A to demonstrate functional involvement of β3-adrenoceptors may lead in many cases to misleading conclusions as they can also interact with other β-adrenoceptor subtypes
or even non-adrenoceptor targets. In conclusion, we propose that many responses attributed to β3-adrenoceptor stimulation may need re-evaluation in the light of the development of more selective tools. Moreover, findings
in experimental animals need to be extended to humans in order to better understand the potential additional indications and
side effects of the β3-adrenoceptor agonists that are beginning to enter clinical medicine.

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    ABSTRACT: β3-Adrenoceptor agonists have recently been introduced for the treatment of the overactive urinary bladder syndrome. Their target, the β3-adrenoceptor, was discovered much later than β1- and β2-adrenoceptors and exhibits unique properties which make extrapolation of findings from the other two subtypes difficult and the β3-adrenoceptor a less understood subtype. This article discusses three aspects of β3-adrenoceptor pharmacology. Firstly, the ligand-recognition profile of β3-adrenoceptors differs considerably from that of the other two subtypes, i.e. many antagonists considered as non-selective actually are β3-sparing including propranolol or nadolol. Many agonists and antagonists classically considered as being β3-selective actually are not, including BRL 37,344 or SR 59,230. Moreover, the binding pocket apparently differs between the human and rodent β3-adrenoceptor, yielding considerable species differences in potency. Second, the expression pattern of β3-adrenoceptors is more restricted than that of other subtypes, particularly in humans; while this makes extrapolation of rodent findings to the human situation difficult, it may result in a smaller potential for side effects. The role of β3-adrenoceptor gene polymorphisms has insufficiently been explored and may differ even between primate species. Third, β3-adrenoceptors lack the phosphorylation sites involved in agonist-induced desensitization of the other two subtypes. Thus, they exhibit down-regulation and/or desensitization in only 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 β3-adrenoceptor as a novel pharmacological target.
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