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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While β1- and β2-adrenoceptor ligands have long assumed key roles in the treatment of various conditions such as coronary heart disease or obstructive airway disease, compounds acting on β3-adrenoceptors are only now undergoing a metamorphosis from experimental tools into therapeutic drugs, e.g., in the treatment of the overactive bladder syndrome (Chapple et al. 2008). The introduction of a new class of drugs is exciting but also generates uncertainty about possible safety and tolerability issues associated with this drug class. The determination of tissues where β3-adrenoceptors play a role has long been hampered by the lack of highly selective agonists and antagonists (Vrydag and Michel 2007). In this issue of the journal, Mori et al. report β3-adrenoceptor-mediated vasodilatation in rat retinal blood vessels in vivo (Mori et al. 2010). Their study expands our knowledge of tissue functions mediated by β3-adrenoceptors but also highlights the methodological challenges in this field. Against this background, we will briefly mention those tissues in which functional β3-adrenoceptors have been demonstrated with various degrees of certainty and discuss the implications for the therapeutic use of agonists acting at these receptors. This discussion will largely be based on examples and does not attempt to be comprehensive. Where possible, we will primarily focus on human tissues. Fields that have been extensively reviewed recently will only be mentioned briefly.
At the mRNA level, β3-adrenoceptors have been found in a range of human tissues including brown and white adipose tissue, small and large intestine, gall bladder, urinary bladder, and brain with low levels in heart and colon; no mRNA was detected in quadriceps and abdominal muscle, liver, lung, kidney, thyroid, or lymphocytes (Berkowitz et al. 1995; Krief et al. 1993; Otsuka et al. 2008). Studies in rats have detected β3-adrenoceptor mRNA mainly in brown and white adipose tissue, in various segments of the gastrointestinal tract, and in the urinary bladder (Cohen et al. 1995; Evans et al. 1996; Fujimura et al. 1999; Roberts et al. 1999), but as in humans, it is also present in brain (Summers et al. 1995). Antibody-based detection of β3-adrenoceptor expression at the protein level has been reported in human gall bladder, colon, prostate, right atrium, and gastrocnemius muscle, whereas no labelling was detected in lung, left ventricle, appendix, uterus, or thyroid (Chamberlain et al. 1999). Detection in adipose tissue from breast, perirenal, and axillary sites proved inconclusive due to problems of interpreting labelling of the thin-walled adipocytes (Chamberlain et al. 1999). While this study provided some validation of antibody selectivity, more recent data raise doubts about the validity of many other receptor antibodies (Michel et al. 2009), including those acting on β-adrenoceptor subtypes (Hamdani and van der Velden 2009; Pradidarcheep et al. 2009).
Based on rodent data, β3-adrenoceptors have long been associated with the promotion of lipolysis in adipocytes, mostly in brown adipose tissue. These findings have prompted drug discovery programmes in the fields of obesity and type 2 diabetes that have yielded disappointing results (Arch 2008) at least partly due to the distinct difference between the rodent and human pharmacophore, which led to the development of several drugs (e.g., BRL 37,344, CL 316,243) that were highly effective and selective in rodents (Arch et al. 1984; Bloom et al. 1992) but with little selectivity or efficacy in humans. The explanation that was adopted initially was that β3-adrenoceptors play an important role in rodent lipolysis but have a much smaller role in humans (Arner et al. 1991; Thomas and Liggett 1993). However, recent findings question this assumption and strongly suggest that there is metabolically active brown fat in humans (Nedergaard et al. 2007). Nevertheless, there is still debate as to whether and to what extent the metabolic effects of catecholamines in humans are mediated through β1- or β3-adrenoceptors (Nedergaard and Cannon 2010). If anything, the metabolic effects of β3-adrenoceptor agonists are likely to be beneficial in humans, but whether the extent of such effects is clinically relevant cannot be determined with certainty based upon the present data.
In contrast, β3-adrenoceptors play an important role in the urinary bladder of humans, likely to an even greater extent than in some animal species (Michel and Vrydag 2006). Within the urinary bladder, they mediate smooth muscle relaxation (Michel and Parra 2008), but they may also affect the function of the urothelium (Masunaga et al. 2010; Otsuka et al. 2008) and afferent nerves (Aizawa et al. 2010). Accordingly, the β3-adrenoceptor agonist mirabegron, previously known as YM-178, has shown efficacy in a clinical proof of concept study in patients with overactive bladder (Chapple et al. 2008) and is now in the late stages of clinical development for this indication. β3-Adrenoceptors may also play a role in the relaxation of human ureter (Park et al. 2000; Tomiyama et al. 2003; Wanajo et al. 2004), urethra (Yamanishi et al. 2003), and penis smooth muscle (Cirino et al. 2003).
β3-Adrenoceptors have also been proposed to play a role in the cardiovascular system, but the evidence for their role remains equivocal, particularly in humans. Thus, several studies have proposed functional β3-adrenoceptors in the rodent heart, which in contrast to β1- and β2-adrenoceptors may mediate negative inotropic effects (Rozec and Gauthier 2006). β3-Adrenoceptors mediating positive inotropic effects have been proposed in the human heart (Gauthier et al. 1996; Pott et al. 2003; Skeberdis et al. 2008), but other studies have failed to demonstrate this finding (Christ et al. 2010; Ikezono et al. 1987). On the other hand, reports of vasodilatation mediated by β3-adrenoceptors are more consistent (Guimaraes and Moura 2001; Rozec and Gauthier 2006), although the vast majority of these findings come from experimental animals that exhibit major intertissue and interspecies differences that make extrapolation to humans difficult. The study by Mori et al. (2010) adds interesting information in this regard as it demonstrates β3-adrenoceptor-mediated vasodilatation in retinal vessels based on drugs with validated selectivity at human subtypes such as the antagonist L-748,337. On the other hand, the same study also shows that concomitant systemic vasodilatation by putative β3-adrenoceptor agonists such as BRL 37,344 or CL 316,243, assessed as blood pressure reductions, is largely, if not completely, mediated by β1- or β2-adrenoceptors, being inhibited by propranolol but not L-748,337 (Mori et al. 2010). While these data suggest that there may be therapeutic potential for β3-adrenoceptor agonists in the treatment of diabetic retinopathy, it remains to be confirmed whether this can be extrapolated to humans. Moreover, based upon the expression of functional β3-adrenoceptors in retinal endothelial cells (Steinle et al. 2003), it remains to be determined whether vasodilatation of retinal vessels primarily involves smooth muscle or endothelium. Potential effects of β3-adrenoceptor agonists on the systemic circulation and the heart remain to be studied in more detail in humans, particularly with regard to a possible risk of hypotension and/or arrhythmia.
In line with the β3-adrenoceptor mRNA expression in the gastrointestinal tract of rats (Evans et al. 1996) and humans (Roberts et al. 1997), various investigators have proposed the presence of functional receptors (largely based on rat and guinea pig studies) in the esophagus (de Boer et al. 1995; Lezama et al. 1996; Oostendorp et al. 2004), stomach (McLaughlin and MacDonald 1991) (Cohen et al. 1995; Horinouchi and Koike 2001), and small and large intestine (Bond and Clarke 1988; Hoey et al. 1996; Horinouchi and Koike 2001; Roberts et al. 1997; Roberts et al. 1999). Generally, β3-adrenoceptor agonists mediate smooth muscle relaxation in these tissues including human colon (Roberts et al. 1997). Accordingly, in in vivo studies, β3-adrenoceptor agonists slowed transit time in wild-type but not β3-adrenoceptor knockout mice (Fletcher et al. 1998). On the other hand, the β3-adrenoceptor agonist solabegron did not significantly alter human colonic transit during a 7-day administration (Grudell et al. 2008). Additional effects on the gastrointestinal tract included reports of enhanced gastric blood flow (Kuratani et al. 1994) and reduced gastric acid secretion (Coruzzi and Bertaccini 1997), leading to protection against gastric ulcers in experimental animals. Moreover, a β3-adrenoceptor agonist was reported to improve colitis in a rat model (Vasina et al. 2008). Functional β3-adrenoceptors have also been proposed in the gall bladder (Oriowo and Thulesius 1999) and in pancreas (Atef et al. 1996). Based on these results, some β3-adrenoceptor agonists may cause constipation, but they may also have protective effects against gastric ulcers and/or colitis.
Outside the abovementioned systems, functional β3-adrenoceptors have also been proposed in myometrium (Bardou et al. 2000; Bardou et al. 2007; Rouget et al. 2004). Whether responses to β3-adrenoceptor agonists are less prone to desensitization than β2-adrenoceptor agonists when used for tocolytic treatment remains to be established. β3-Adrenoceptors were also proposed in skeletal muscle (Roberts et al. 1993) and in the brain, where they apparently can mediate important effects in animal models of memory, anxiety, and depression (Gibbs et al. 2010; Hutchinson et al. 2007; Stemmelin et al. 2008). The latter effect may become useful therapeutically for agonists with good penetration into the brain.
Of note, most of the above studies have relied on the use of agonists and/or antagonists with little selectivity for this subtype such as SR59230A (Vrydag and Michel 2007). As highlighted by the study in this issue (Mori et al. 2010) and other recent data (Ngala et al. 2009), agonists such as BRL 37,344 or CL 316,243 can activate not only β3-adrenoceptors but also other β-adrenoceptor subtypes and possibly nonadrenoceptor targets. While SR59230A has relatively high affinity for β3-adrenoceptors in contrast to many classical β-adrenoceptor antagonists, it has at least similar, if not slightly higher, affinity for human β1- and β2-adrenoceptors and can be a partial agonist at β3-adrenoceptors (Vrydag and Michel 2007). Therefore, most of the above studies have to be interpreted carefully in the light of the selectivity of the tools on which they are based. At present, L-748,337 appears to be the only widely available antagonist with a well-validated selectivity for human β3-adrenoceptors. Thus, several tissue functions that have until now been assigned to β3-adrenoceptors may require confirmation with these more selective tools. Another issue is that findings in rodents and other experimental animals are an important step but may not necessarily reliably predict findings in humans. For example, β3-adrenoceptors appear to be the predominant if not the only subtype-mediating relaxation of the human urinary bladder, whereas in rats and some other species, this function involves at least one other subtype (Michel and Vrydag 2006). Conversely, β3-adrenoceptors play an important role in rodent lipolysis, but their role is much less clear-cut in humans (Arch 2008).
In addition to off-target effects due to the presence of β3-adrenoceptors in tissues that are not being targeted for a therapeutic effect, it is also increasingly evident that drugs acting at this receptor cannot be classified simply as agonists, partial agonists, or antagonists, and that ligands can induce unique ligand-specific receptor conformations that can result in differential activation of particular signal transduction pathways (Urban et al. 2007), the phenomenon known (amongst other terms) as ligand-directed signaling bias. At the β3-adrenoceptor, L-748,337 is a competitive antagonist for cAMP accumulation but has high agonist potency and efficacy for ERK1/2 phosphorylation. Zinterol, which has agonist properties at the human β3-adrenoceptor (Hutchinson et al. 2006), has high efficacy for cAMP accumulation but lower efficacy than L-748,337 for both ERK1/2 and p38 MAPK phosphorylation (Sato et al. 2008). A similar reversal of efficacy was also seen with CL 316,243 and SR59230A acting at the mouse β3-adrenoceptor (Sato et al. 2007). When the functional readout is cAMP, CL 316,243 is a full agonist and SR59230A either a partial agonist or antagonist depending on the level of receptor expression. In the identical cells, but using extracellular acidification rate as the functional measure, both CL 316,243 and SR59230A are full agonists at all levels of receptor expression. Further analysis with selective MAPK inhibitors confirmed that SR59230A has much higher efficacy than CL 316,243 for MAPK signaling. These examples of reversal of efficacy provide strong support for the concept of ligand-directed signaling (Evans et al. 2010) and suggest that other factors may have to be taken into account when optimizing clinical efficacy of new drugs acting at β3-adrenoceptors.
A final aspect of the study by Mori et al. (2010) merits comment. They show that β2-adrenoceptor-mediated vasodilatation in the general circulation apparently undergoes some desensitization in diabetes, whereas β3-adrenoceptor-mediated vasodilatation in retinal vessels does not. Indeed, the expression and function of β1- and β2-adrenoceptors undergoes extensive desensitization in disease states such as heart failure (Brodde 2007) or upon agonist treatment, e.g., in the context of tocolysis (Frambach et al. 2005), whereas β3-adrenoceptor responses may be much less susceptible to such regulation in most but not all cases (Chaudhry and Granneman 1994; Vrydag et al. 2009).
In conclusion we propose that many responses attributed to β3-adrenoceptor stimulation may need revalidation using truly selective tools. Moreover, findings in experimental animals need to be extended to humans in order to better understand the safety profile of β3-adrenoceptor agonists likely to enter clinical medicine soon.
References
Aizawa N, Igawa Y, Nishizawa O, Wyndaele J-J (2010) Effects of CL316,243, a beta3-adrenoceptor agonist, and intravesical prostaglandin E2 on the primary bladder afferent activity of the rat. Neurourol Urodyn in press
Arch JRS (2008) Perspectives from β3-adrenoceptor agonists on pharmacology, physiology and obesity drug discovery. Naunyn-Schmiedeberg's Arch Pharmacol 378:225–240
Arch JR, Ainsworth AT, Cawthorne MA, Piercy V, Sennitt MV, Thody VE, Wilson C, Wilson S (1984) Atypical beta-adrenoceptor on brown adipocytes as target for anti-obesity drugs. Nature 309:163–165
Arner P, Kriegholm E, Engfeldt P (1991) In vivo interactions between beta-1 and beta-2 adrenoceptors regulate catecholamine tachyphylaxia in human adipose tissue. J Pharmacol Exp Ther 259:317–323
Atef N, Lafontan M, Double A, Helary C, Ktorza A, Penicaud L (1996) A specific β3-adrenoceptor agonist induces pancreatic islet blood flow and insulin secretion in rats. Eur J Pharmacol 298:287–292
Bardou M, Loustalot C, Cortijo J, Simon B, Naline E, Dumas M, Esteve S, Croci T, Chalon P, Frydman R, Sagot P, Manara L, Morcillo EJ, Advenier C (2000) Functional, biochemical and molecular biological evidence for a possible β3-adrenoceptor in human near-term myometrium. Br J Pharmacol 130:1960–1966
Bardou M, Rouget C, Breuiller-Fouche M, Loustalot C, Naline E, Sagot P, Frydman R, Morcillo EJ, Advenier C, Leroy M-J, Morrison JJ (2007) Is the beta3-adrenoceptor (ADRB3) a potential target for uterorelaxant drugs? BMC Pregnancy and Childbirth 7(Suppl 1):S14
Berkowitz DE, Nardone NA, Smiley RM, Price DT, Kreutter DK, Fremeau RT, Schwinn DA (1995) Distribution of β3-adrenoceptor mRNA in human tissues. Eur J Pharmacol 289:223–228
Bloom JD, Dutia MD, Johnson BD, Wissner A, Burns MG, Largis EE, Dolan JA, Claus TH (1992) Disodium (R, R)-5-[2-[[2-(3-chlorophenyl)-2-hydroxyethyl]-amino]propyl]-1, 3-benzodioxole-2, 2-dicarboxylate (CL 316, 243). A potent β-adrenergic agonist virtually specific for β3 receptors. A promising antidiabetic and antiobesity agent. J Med Chem 35:3081–3084
Bond RA, Clarke DE (1988) Agonist and antagonist characterization of a putative adrenoceptor with distinct pharmacological properties from the α- and β-subtypes. Br J Pharmacol 95:723–734
Brodde O-E (2007) β-Adrenoceptor blocker treatment and the cardiac β-adrenoceptor-G-protein(s)-adenylyl cyclase system in chronic heart failure. Naunyn-Schmiedeberg's Arch Pharmacol 374:361–372
Chamberlain PD, Jennings KH, Paul F, Cordell J, Holmes SD, Park J, Chambers J, Sennitt MV, Stock MJ, Cawthorne MA, Young PW, Murphy GJ (1999) The tissue distribution of the human β3-adrenoceptor studied using a monoclonal antibody: direct evidence of the β3-adrenoceptor in human adipose tissue, atrium and skeletal muscle. Int J Obes Relat Metab Disord 23:1057–1065
Chapple CR, Yamaguchi O, Ridder A, Liehne J, Carl S, Mattiasson A, Aramburu MAL, Lucas M, Everaert K (2008) Clinical proof of concept study (Blossom) shows novel β3 adrenoceptor agonist YM178 is effective and well tolerated in the treatment of symptoms of overactive bladder. Eur Urol Suppl 7:239
Chaudhry A, Granneman JG (1994) Influence of cell type upon the desensitization of the β3-adrenergic receptor. J Pharmacol Exp Ther 271:1253–1258
Christ T, Molenaar P, Ravens U, Kaumann AJ (2010) Evidence against beta-3-adrenoceptor-mediated increase in contractile force and L-type Ca2+ current ICa-L in human atrial myocardium at 37°C. Naunyn-Schmiedeberg's Arch Pharmacol 381(suppl 1):15
Cirino G, Sorrentino R, di Villa d'Emmanuele, Bianca R, Popolo A, Palmieri A, Imbimbo C, Fusco F, Longo N, Tajana G, Ignarro LJ, Mirone V (2003) Involvement of β3-adrenergic receptor activation via cyclic GMP- but not NO-dependent mechanisms in human corpus cavernosum function. Proc Natl Acad Sci USA 100:5531–5536
Cohen ML, Granneman JG, Chaudhry A, Schenck KW, Cushing DJ, Palkowitz AD (1995) Is the “atypical” β-receptor in the rat stomach fundus the rat β3 receptor? J Pharmacol Exp Ther 272:446–451
Coruzzi G, Bertaccini G (1997) The β3-adrenoceptor agonist SRsA inhibits gastric acid secretion in the conscious rat. Naunyn-Schmiedeberg's Arch Pharmacol 356:263–265
de Boer REP, Brouwer F, Zaagsma J (1995) Noradrenaline-induced relaxation of rat oesophageal muscularis mucosae: mediation solely by innervated β3-adrenoceptors. Br J Pharmacol 116:1945–1947
Evans BA, Papaioannou M, Bonazzi VR, Summers RJ (1996) Expression of β3-adrenoceptor mRNA in rat tissues. Br J Pharmacol 117:210–216
Evans BA, Sato M, Sarwar M, Hutchinson DS, Summers RJ (2010) Ligand-directed signalling at β-adrenoceptors. Br J Pharmacol 159:1022–1038
Fletcher DS, Candelore MR, Grujic D, Lowell BB, Luell S, Susulic VS, Macintyr DE (1998) Beta-3 adrenergic receptor agonists cause an increase in gastrointestinal transit time in wild-type mice, but not in mice lacking the beta-3 adrenergic receptor. J Pharmacol Exp Ther 287:720–724
Frambach T, Müller T, Freund S, Engelhardt S, Sutterlin M, Lohse MJ, Dietl J (2005) Self-limitation of intravenous tocolysis with β2-adrenergic agonists Is mediated through receptor G protein uncoupling. J Clin Endocrinol Metab 90:2882–2887
Fujimura T, Tamura K, Tsutsumi T, Yamamoto T, Nakamura K, Koibuchi Y, Kobayashi M, Yamaguchi O (1999) Expression and possible functional role of the β3-adrenoceptor in human and rat detrusor muscle. J Urol 161:680–685
Gauthier C, Tavernier G, Charpentier F, Langin D, Le Marec H (1996) Functional β3-adrenoceptor in the human heart. J Clin Invest 98:556–562
Gibbs ME, Maksel D, Gibbs Z, Hou X, Summers RJ, Small DH (2010) Memory loss caused by β-amyloid protein is rescued by a β3-adrenoceptor agonist. Neurobiol Aging 31:614–624
Grudell ABM, Camilleri M, Jensen KL, Foxx-Orenstein AE, Burton DD, Ryks MD, Baxter KL, Cox DS, Dukes GE, Kelleher DL, Zinsmeister AR (2008) Dose-response effect of a β3-adrenergic receptor agonist, solabegron, on gastrointestinal transit, bowel function, and somatostatin levels in health. Am J Physiol 294:G1114–G1119
Guimaraes S, Moura D (2001) Vascular adrenoceptors: an update. Pharmacol Rev 53:319–356
Hamdani N, van der Velden J (2009) Lack of specificity of antibodies directed against human beta-adrenergic receptors. Naunyn-Schmiedeberg's Arch Pharmacol 379:403–407
Hoey A, Jackson C, Pegg G, Sillence M (1996) Atypical responses of rat ileum to pindolol, cyanopindolol and iodocyanopindolol. Br J Pharmacol 117:712–716
Horinouchi T, Koike K (2001) Agonist activity of SR59230A at atypical β-adrenoceptors in guinea pig gastric fundus and duodenum. Eur J Pharmacol 416:165–168
Hutchinson DS, Chernogubova E, Sato M, Summers RJ, Bengtsson T (2006) Agonist effects of zinterol at the mouse and human β3-adrenoceptor. Naunyn-Schmiedeberg's Arch Pharmacol 373:158–168
Hutchinson DS, Summers RJ, Gibbs ME (2007) β2- and β3-adrenoceptors activate glucose uptake in chick astrocytes by distinct mechanisms: a mechanism for memory enhancement? J Neurochem 103:997–1008
Ikezono K, Michel MC, Zerkowski H-R, Beckeringh JJ, Brodde O-E (1987) The role of cyclic AMP in the positive inotropic effect mediated by β1- and β2-adrenoceptors in the isolated human right atrium. Naunyn-Schmiedeberg's Arch Pharmacol 335:561–566
Krief S, Lönnqvist F, Raimbault S, Baude B, van Spronsen A, Arner P, Strosberg AD, Ricquier D, Emorine LJ (1993) Tissue distribution of beta 3-adrenergic receptor mRNA in man. J Clin Invest 91:344–349
Kuratani K, Kodama H, Yamaguchi I (1994) Enhancement of gastric mucosal blood flow by beta-3 adrenergic agonists prevents indomethacin-induced antral ulcer in the rat. J Pharmacol Exp Ther 270:559–565
Lezama EJ, Konkar AA, Salazar-Bookaman MM, Miller DD, Feller DR (1996) Pharmacological study of atypical β-adrenoceptors in rat esophageal smooth muscle. Eur J Pharmacol 308:69–80
Masunaga K, Chapple CR, McKay NG, Yoshida M, Sellers DJ (2010) The β3-adrenoceptor mediates the inhibitory effects of β-adrenoceptor agonists via the urothelium in pig bladder dome. Neurourol Urodyn in press
McLaughlin DP, MacDonald A (1991) Characterization of catecholamine-mediated relaxations in rat isolated gastric fundus: evidence for an atypical β-adrenoceptor. Br J Pharmacol 103:1351–1356
Michel MC, Parra S (2008) Similarities and differences in the autonomic control of airway and urinary bladder smooth muscle. Naunyn-Schmiedeberg's Arch Pharmacol 378:217–224
Michel MC, Vrydag W (2006) α1-, α2- and β-adrenoceptors in the urinary bladder, urethra and prostate. Br J Pharmacol 147:S88–S119
Michel MC, Wieland T, Tsujimoto G (2009) How reliable are G-protein-coupled receptor antibodies? Naunyn-Schmiedeberg's Arch Pharmacol 377:385–388
Mori A, Miwa T, Sakamoto K, Nakahara T, Ishii K (2010) Pharmacological evidence for the presence of functional β3-adrenoceptors in rat retinal blood vessels. Naunyn-Schmiedeberg's Arch Pharmacol in press
Nedergaard J, Cannon B (2010) The changed metabolic world with human brown adipose tissue: therapeutic visions. Cell Metabolism 11:268–272
Nedergaard J, Bengtsson T, Cannon B (2007) Unexpected evidence for active brown adipose tissue in adult humans. Am J Physiol 293:E444–E452
Ngala RA, O'Dowd J, Wang SJ, Stocker C, Cawthorne MA, Arch JRS (2009) β2-Adrenoceptors and non-β-adrenoceptors mediate effects of BRL37344 and clenbuterol on glucose uptake in soleus muscle: studies using knockout mice. Br J Pharmacol 158:1676–1682
Oostendorp J, Obels PP, Terpstra AR, Nelemans SA, Zaagsma J (2004) Modulation of β2- and β3-adrenoceptor-mediated relaxation of rat oesophagus smooth muscle by protein kinase C. Eur J Pharmacol 495:75–81
Oriowo MA, Thulesius O (1999) Functional characterization of β-adrenoceptors mediating relaxation in sheep gallbladder. Fundam Clin Pharmacol 13:187–192
Otsuka A, Shinbo H, Matsumoto R, Kurita Y, Ozono S (2008) Expression and functional role of β-adrenoceptors in the human urinary bladder. Naunyn-Schmiedeberg's Arch Pharmacol 377:473–481
Park Y-C, Tomiyama Y, Hayakawa K, Akahane M, Ajisawa Y, Miyatake R, Kiwamoto H, Sugiyama T, Kurita T (2000) Existence of a β3-adrenoceptor and its functional role in the human ureter. J Urol 164:1364–1370
Pott C, Brixius K, Bundkirchen A, Bölck B, Bloch W, Steinritz D, Mehlhorn U, Schwinger RHG (2003) The preferential β3-adrenoceptor agonist BRL 37344 increases force via β1-/β2-adrenoceptors and induces endothelial nitric oxide synthase via β3-adrenoceptors in human atrial myocardium. Br J Pharmacol 138:521–529
Pradidarcheep W, Stallen J, Labruyere WT, Dabhoiwala NF, Michel MC, Lamers WH (2009) Lack of specificity of commercially available antisera against muscarinic and adrenergic receptors. Naunyn-Schmiedeberg's Arch Pharmacol 379:397–402
Roberts SJ, Molenaar P, Summers RJ (1993) Characterization of propranolol-resistant (–)-[125I]-cyanopindolol binding sites in rat soleus muscle. Br J Pharmacol 109:344–352
Roberts SJ, Papaioannou M, Evans BA, Summers RJ (1997) Functional and molecular evidence for β1-, β2- and β3-adrenoceptors in human colon. Br J Pharmacol 120:1527–1535
Roberts SJ, Papaioannou M, Evans BA, Summers RJ (1999) Characterization of β-adrenoceptor mediated smooth muscle relaxation and the detection of mRNA for β1-, β2- and β3-adrenoceptors in rat ileum. Br J Pharmacol 127:949–961
Rouget C, Breullier-Fouche M, Mercier FJ, Leroy MJ, Loustalot C, Naline E, Frydman R, Croci T, Morcillo EJ, Advenier C, Bardou M (2004) The human near-term myometrial β3-adrenoceptor but not the β2-adrenoceptor is resistant to desensitisation after sustained agonist stimulation. Br J Pharmacol 141:831–841
Rozec B, Gauthier C (2006) β3-Adrenoceptors in the cardiovascular system: putative roles in human pathologies. Pharmacol Ther 111:652–673
Sato M, Horinouchi T, Hutchinson DS, Evans BA, Summers RJ (2007) Ligand-directed signaling at the β3-adrenoceptor produced by SR59230A relative to receptor agonists. Mol Pharmacol 74:1359–1368
Sato M, Hutchinson DS, Evans BA, Summers RJ (2008) The β3-adrenoceptor agonist 4-[[(Hexylamino)carbonyl]amino]-N-[4-[2-[[(2S)-2-hydroxy-3-(4-hydroxyphenoxy)propyl]amino]ethyl]-phenyl]-benzenesulfonamide (L755507) and antagonist (S)-N-[4-[2-[[3-[3-(acetamidomethyl)phenoxy]-2-hydroxypropyl]amino]-ethyl]phenyl]benzenesulfonamide (L748337) activate different signaling pathways in Chinese hamster ovary-K1 cells stably expressing the human β3-adrenoceptor. Mol Pharmacol 74:1417–1428
Skeberdis VA, Gendviliene V, Zablockaite D, Teinys R, Macianskiene R, Bogdelis A, Jurevicius J, Fischmeister R (2008) β3-Adrenergic receptor activation increases human atrial tissue contractility and stimulates the L-type Ca2+ current. J Clin Invest 118:3219–3227
Steinle JJ, Booz GW, Meininger CJ, Day JNE, Granger HJ (2003) β3-Adrenergic receptors regulate retinal endothelial cell migration and proliferation. J Biol Chem 278:20681–20686
Stemmelin J, Cohen C, Terranova J-P, Lopez-Grancha M, Pichat P, Bergis O, Decobert M, Santucci V, Francon D, Alonso R, Stahl SM, Keane P, Avenet P, Scatton B, Le Fur G, Griebel G (2008) Stimulation of the β3-adrenoceptor as a novel treatment strategy for anxiety and depressive disorders. Neuropsychopharmacol 33:574–587
Summers RJ, Papaioannou M, Harris S, Evans BA (1995) Expression of β3-adrenoceptor mRNA in rat brain. Br J Pharmacol 116:2547–2548
Thomas RF, Liggett SB (1993) Lack of β3-adrenergic receptor mRNA expression in adipose and other metabolic tissues in the adult human. Mol Pharmacol 43:343–348
Tomiyama Y, Murakami M, Yamazaki Y, Kojima M, Akahane M (2003) Comparison between CL-316243- and CGP-12177A-induced relaxations in isolated canine ureter. Pharmacology 68:140–146
Urban JD, Clarke WP, von Zastrow M, Nichols DE, Kobilka B, Weinstein H, Javitch JA, Roth BL, Christopoulos A, Sexton PM, Miller KJ, Spedding M, Mailman RB (2007) Functional selectivity and classical concepts of quantitative pharmacology. J Pharmacol Exp Ther 320:1–13
Vasina V, Abu-Gharbieh E, Barbara G, De Giorgio R, Colucci R, Blandizzi C, Bernardini N, Croci T, Del Tacca M, De Ponti F (2008) The β3-adrenoceptor agonist SR58611A ameliorates experimental colitis in rats. Neurogastroenterol Motil 20:1030–1041
Vrydag W, Michel MC (2007) Tools to study β3-adrenoceptors. Naunyn-Schmiedeberg's Arch Pharmacol 374:385–398
Vrydag W, Alewijnse AE, Michel MC (2009) Agonist-induced desensitization of human β3-adrenoceptors expressed in CHO or HEK293 cells. Naunyn-Schmiedeberg's Arch Pharmacol 379:213
Wanajo I, Tomiyama Y, Yamazaki Y, Kojima M, Shibata N (2004) Pharmacological characterization of β-adrenoceptor subtypes mediating relaxation in porcine isolated uretreral smooth muscle. J Urol 172:1155–1159
Yamanishi T, Chapple CR, Yasuda K, Yoshida K, Chess-Williams R (2003) The functional role of β-adrenoceptor subtypes in mediating relaxation of pig urethral smooth muscle. J Urol 170:2508–2511
Acknowledgement/conflict of interest
MCM has received research funds and consultancy honoraria from Astellas and Boehringer Ingelheim in this area. Work in his laboratory is also supported through Coordination Theme 1 (Health) of the European Community's FP7, Grant agreement number HEALTH-F2-2008–223234. RJS is supported by National Health and Medical Research Council (NHMRC) of Australia Project Grant 436713 and Program Grant 519461.
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Open Access This is an open access article distributed under the terms of the Creative Commons Attribution Noncommercial License (https://creativecommons.org/licenses/by-nc/2.0), which permits any noncommercial use, distribution, and reproduction in any medium, provided the original author(s) and source are credited.
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Michel, M.C., Ochodnicky, P. & Summers, R.J. Tissue functions mediated by β3-adrenoceptors—findings and challenges. Naunyn-Schmied Arch Pharmacol 382, 103–108 (2010). https://doi.org/10.1007/s00210-010-0529-2
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DOI: https://doi.org/10.1007/s00210-010-0529-2