The new radioligand [3H]-L 748,337 differentially labels human and rat β3-adrenoceptors

Wieringen, Jan-Peter van; Michel-Reher, Martina B.; Hatanaka, Toshiki; Ueshima, Koji; Michel, Martin C.

doi:10.1016/j.ejphar.2013.10.039

Cited by 25 publications

(22 citation statements)

References 39 publications

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“…Moreover, the antibody Sc1473 has been reported to yield a specific band in mouse heart, which was absent in β 3 -adrenoceptor knockout mice (Bundgaard et al 2010). As the latter antibody had been found to be invalid for use with human β 3 -adrenoceptors (Pradidarcheep et al 2009), we hypothesized that β 3 -adrenoceptor selectivity may be species-dependent, similar to that of some small molecule ligands at this receptor (Nahmias et al 1991;Liggett 1992;van Wieringen et al 2013). Therefore, the present study was designed to further evaluate the target selectivity of AB15688 and Sc1473 for the rodent β 3 -adrenoceptor.…”

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confidence: 96%

Rat β3-adrenoceptor protein expression: antibody validation and distribution in rat gastrointestinal and urogenital tissues

Cernecka

Pradidarcheep

Lamers

et al. 2014

Naunyn-Schmiedeberg's Arch Pharmacol

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β3-Adrenoceptors play important roles in the regulation of urogenital and probably gastrointestinal function. However, despite recent progress, their detection at the protein level has remained difficult due to a lack of sufficiently validated selective antibodies. Therefore, we have explored the selectivity of two antibodies for the detection of rodent β3-adrenoceptors in immunoblots and immunohistochemistry. Of two reportedly promising candidates, antibody AB15688 did not exhibit subtype selectivity in immunoblots. In contrast, the antibody Sc1473 exhibited at least some selectivity in immunoblots and more promising results in immunocytochemical and immunohistochemical stains in cells transfected with cloned β-adrenoceptor subtypes and in rat and mouse tissues. In a systematic screening of rat gastrointestinal and urogenital tissues, Sc1473 produced selective staining in the epithelial cell lining of the stomach and the urothelium of ureter and bladder. We conclude that the two tested antibodies are inappropriate or at least insufficient for immunoblotting applications, but Sc1473 appears to be useful for immunohistochemical detection of β3-adrenoceptor protein in rodent tissues. The β3-adrenoceptor protein exhibits a distinct expression pattern in the rat gastrointestinal and urogenital tract, which is at least partly in line with previously reported functional data.

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confidence: 96%

Rat β3-adrenoceptor protein expression: antibody validation and distribution in rat gastrointestinal and urogenital tissues

Cernecka

Pradidarcheep

Lamers

et al. 2014

Naunyn-Schmiedeberg's Arch Pharmacol

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“…Indeed, in radioligand binding studies with cloned human subtypes, it exhibited much higher affinity for b 3 -than b 1 -or b 2 -adrenoceptors (K i 4 vs. 390 and 204 nM, respectively) (Candelore et al, 1999). Accordingly, a tritiated version of L 748,337 has been proposed to be a b 3 -selective radioligand in studies with human receptors (van Wieringen et al, 2013). However, the latter studies also identified two possible problems in using L 748,337.…”

Section: Unique Ligand Recognition Profilementioning

confidence: 99%

“…Expression studies at the protein level have long been hampered by a lack of target selectivity of many b 3 -adrenoceptor antibodies (Cernecka et al, 2012). Suitable radioligands have also been missing until recently (van Wieringen et al, 2013). Therefore, most tissue mapping has relied on functional studies.…”

Section: Receptor Polymorphisms and Expression Patternmentioning

confidence: 99%

“…For instance, the agonist BRL 37,344 (Nahmias et al, 1991;Liggett, 1992), the weak partial agonist CGP 12,177 (((-)-4-(3-t-butylamino-2-hydroxypropoxy)- [5, H]benzimidazole-2-one) (Liggett, 1992), and the antagonist/ biased agonist L 748,337 (Candelore et al, 1999;van Wieringen et al, 2013) exhibit affinity differences of 10-fold or more between rat and human or rat and rhesus monkey b 3 -adrenoceptors, indicating important species differences in the ligand binding pocket; a better understanding of such difference awaits, resolving the crystal structure of b 3 -adrenoceptors. Based on such species differences, several investigators have turned to monkeys to explore properties of novel b 3 -adrenoceptor agonists (Maruyama et al, 2012;Hatanaka et al, 2013).…”

Section: Unique Ligand Recognition Profilementioning

confidence: 99%

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The Odd Sibling: Features ofβ₃-Adrenoceptor Pharmacology

2014

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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.

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“…The only non-invasive way to rule out this scenario was to consider the possible pharmacologic modulation of metabolic signal. To this purpose, we selected the unselective propranolol whose action on beta-3 receptors has been already documented [15,16], although the effectiveness of other beta-blockers was not tested. The inclusion of this possibility in the differential diagnosis and planning functional imaging procedures was, in this case, the key for this diagnosis.…”

Section: Discussionmentioning

confidence: 99%

Functional Diagnosis of Hibernoma by FDG Imaging Under Propranolol Treatment: A Case Report

E¹

2015

J Health Med Informat

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The new radioligand [3H]-L 748,337 differentially labels human and rat β3-adrenoceptors

Cited by 25 publications

References 39 publications

Rat β3-adrenoceptor protein expression: antibody validation and distribution in rat gastrointestinal and urogenital tissues

Rat β3-adrenoceptor protein expression: antibody validation and distribution in rat gastrointestinal and urogenital tissues

The Odd Sibling: Features ofβ₃-Adrenoceptor Pharmacology

Functional Diagnosis of Hibernoma by FDG Imaging Under Propranolol Treatment: A Case Report

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The new radioligand [3H]-L 748,337 differentially labels human and rat β3-adrenoceptors

Cited by 25 publications

References 39 publications

Rat β3-adrenoceptor protein expression: antibody validation and distribution in rat gastrointestinal and urogenital tissues

Rat β3-adrenoceptor protein expression: antibody validation and distribution in rat gastrointestinal and urogenital tissues

The Odd Sibling: Features ofβ3-Adrenoceptor Pharmacology

Functional Diagnosis of Hibernoma by FDG Imaging Under Propranolol Treatment: A Case Report

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The Odd Sibling: Features ofβ₃-Adrenoceptor Pharmacology