Beta-3 adrenergic receptor explained

The beta-3 adrenergic receptor (β₃-adrenoceptor), also known as ADRB3, is a beta-adrenergic receptor, and also denotes the human gene encoding it.^[1]

Function

Actions of the β₃ receptor include

• Enhancement of lipolysis in adipose tissue.^[2]
• Thermogenesis in skeletal muscle^[3]

It is located mainly in adipose tissue and is involved in the regulation of lipolysis and thermogenesis. Some β₃ agonists have demonstrated antistress effects in animal studies, suggesting it also has a role in the central nervous system (CNS). β₃ receptors are found in the gallbladder, urinary bladder, and in brown adipose tissue. Their role in gallbladder physiology is unknown, but they are thought to play a role in lipolysis and thermogenesis in brown fat. In the urinary bladder it is thought to cause relaxation of the bladder and prevention of urination.^[4]

Mechanism of action

Beta adrenergic receptors are involved in the epinephrine- and norepinephrine-induced activation of adenylate cyclase through the action of the G proteins of the type G_s.^[1]

Ligands

Agonists

• Amibegron (SR-58611A)^{[5] [6]}
• BRL-37344^[7]
• CL-316,243^[8]
• L-742,791^[9]
• L-796,568^[10]
• LY-368,842
• Mirabegron (YM-178),^[11] approved for treatment of overactive bladder in Japan, United States, UK, Canada, China and India.
• Nebivolol^[12] selective beta(1)-blocker and beta(3)-agonist.
• Ro40-2148
• Solabegron (GW-427,353)^[13]
• Vibegron (MK-4618)^[14]

Antagonists

• L-748,328
• L-748,337
• SR 59230A was thought to be a selective β₃ antagonist^[15] but later found to also be an antagonist of the α₁ receptor.^[16]

Interactions

Beta-3 adrenergic receptor has been shown to interact with Src.^[17]

See also

• Other adrenergic receptors
  • Alpha-1 adrenergic receptor
  • Alpha-2 adrenergic receptor
  • Beta-1 adrenergic receptor
  • Beta-2 adrenergic receptor
• Beta blocker

Further reading

• Granneman JG, Lahners KN, Rao DD . Rodent and human beta 3-adrenergic receptor genes contain an intron within the protein-coding block . Mol. Pharmacol. . 42 . 6 . 964–70 . 1993 . 1336117 .
• Nahmias C, Blin N, Elalouf JM, Mattei MG, Strosberg AD, Emorine LJ . Molecular characterization of the mouse beta 3-adrenergic receptor: relationship with the atypical receptor of adipocytes . EMBO J. . 10 . 12 . 3721–7 . 1991 . 1718744 . 453106 . 10.1002/j.1460-2075.1991.tb04940.x.
• Emorine LJ, Marullo S, Briend-Sutren MM, Patey G, Tate K, Delavier-Klutchko C, Strosberg AD . Molecular characterization of the human beta 3-adrenergic receptor . Science . 245 . 4922 . 1118–21 . 1989 . 2570461 . 10.1126/science.2570461 . 1989Sci...245.1118E .
• Guan XM, Amend A, Strader CD . Determination of structural domains for G protein coupling and ligand binding in beta 3-adrenergic receptor . Mol. Pharmacol. . 48 . 3 . 492–8 . 1995 . 7565630 .
• Rodriguez M, Carillon C, Coquerel A, Le Fur G, Ferrara P, Caput D, Shire D . Evidence for the presence of beta 3-adrenergic receptor mRNA in the human brain . Brain Res. Mol. Brain Res. . 29 . 2 . 369–75 . 1995 . 7609625 . 10.1016/0169-328X(94)00274-I .
• Clément K, Vaisse C, Manning BS, Basdevant A, Guy-Grand B, Ruiz J, Silver KD, Shuldiner AR, Froguel P, Strosberg AD . Genetic variation in the beta 3-adrenergic receptor and an increased capacity to gain weight in patients with morbid obesity . N. Engl. J. Med. . 333 . 6 . 352–4 . 1995 . 7609752 . 10.1056/NEJM199508103330605 . free .
• Dib A, Adélaïde J, Chaffanet M, Imbert A, Le Paslier D, Jacquemier J, Gaudray P, Theillet C, Birnbaum D, Pébusque MJ . Characterization of the region of the short arm of chromosome 8 amplified in breast carcinoma . Oncogene . 10 . 5 . 995–1001 . 1995 . 7898940 .
• Mahmoudian M . The complex of human Gs protein with the beta 3 adrenergic receptor: a computer-aided molecular modeling study . Journal of Molecular Graphics . 12 . 1 . 22–8, 34 . 1994 . 8011597 . 10.1016/0263-7855(94)80004-9 .
• Wilkie TM, Chen Y, Gilbert DJ, Moore KJ, Yu L, Simon MI, Copeland NG, Jenkins NA . Identification, chromosomal location, and genome organization of mammalian G-protein-coupled receptors . Genomics . 18 . 2 . 175–84 . 1994 . 8288218 . 10.1006/geno.1993.1452 .
• Krief S, Lönnqvist F, Raimbault S, Baude B, Van Spronsen A, Arner P, Strosberg AD, Ricquier D, Emorine LJ . Tissue distribution of beta 3-adrenergic receptor mRNA in man . J. Clin. Invest. . 91 . 1 . 344–9 . 1993 . 8380813 . 330032 . 10.1172/JCI116191 .
• van Spronsen A, Nahmias C, Krief S, Briend-Sutren MM, Strosberg AD, Emorine LJ . The promoter and intron/exon structure of the human and mouse beta 3-adrenergic-receptor genes . Eur. J. Biochem. . 213 . 3 . 1117–24 . 1993 . 8389293 . 10.1111/j.1432-1033.1993.tb17861.x . free .
• Lelias JM, Kaghad M, Rodriguez M, Chalon P, Bonnin J, Dupre I, Delpech B, Bensaid M, LeFur G, Ferrara P . Molecular cloning of a human beta 3-adrenergic receptor cDNA . FEBS Lett. . 324 . 2 . 127–30 . 1993 . 8389717 . 10.1016/0014-5793(93)81377-C . 84702667 . free .
• Candelore MR, Deng L, Tota LM, Kelly LJ, Cascieri MA, Strader CD . Pharmacological characterization of a recently described human beta 3-adrenergic receptor mutant . Endocrinology . 137 . 6 . 2638–41 . 1996 . 8641219 . 10.1210/endo.137.6.8641219 . free .
• Fujisawa T, Ikegami H, Yamato E, Takekawa K, Nakagawa Y, Hamada Y, Oga T, Ueda H, Shintani M, Fukuda M, Ogihara T . Association of Trp64Arg mutation of the beta3-adrenergic-receptor with NIDDM and body weight gain . Diabetologia . 39 . 3 . 349–52 . 1996 . 8721782 . 10.1007/BF00418352 . 24270803 .
• Higashi K, Ishikawa T, Ito T, Yonemura A, Shige H, Nakamura H . Association of a genetic variation in the beta 3-adrenergic receptor gene with coronary heart disease among Japanese . Biochem. Biophys. Res. Commun. . 232 . 3 . 728–30 . 1997 . 9126344 . 10.1006/bbrc.1997.6339 .
• Hoffstedt J, Poirier O, Thörne A, Lönnqvist F, Herrmann SM, Cambien F, Arner P . Polymorphism of the human beta3-adrenoceptor gene forms a well-conserved haplotype that is associated with moderate obesity and altered receptor function . Diabetes . 48 . 1 . 203–5 . 1999 . 9892244 . 10.2337/diabetes.48.1.203 .
• Halushka MK, Fan JB, Bentley K, Hsie L, Shen N, Weder A, Cooper R, Lipshutz R, Chakravarti A . Patterns of single-nucleotide polymorphisms in candidate genes for blood-pressure homeostasis . Nat. Genet. . 22 . 3 . 239–47 . 1999 . 10391210 . 10.1038/10297 . 4636523 .
• Kimura K, Sasaki N, Asano A, Mizukami J, Kayahashi S, Kawada T, Fushiki T, Morimatsu M, Yoshida T, Saito M . Mutated human beta3-adrenergic receptor (Trp64Arg) lowers the response to beta3-adrenergic agonists in transfected 3T3-L1 preadipocytes . Horm. Metab. Res. . 32 . 3 . 91–6 . 2000 . 10786926 . 10.1055/s-2007-978597 . 260166451 .
• Cao W, Luttrell LM, Medvedev AV, Pierce KL, Daniel KW, Dixon TM, Lefkowitz RJ, Collins S . Direct binding of activated c-Src to the beta 3-adrenergic receptor is required for MAP kinase activation . J. Biol. Chem. . 275 . 49 . 38131–4 . 2001 . 11013230 . 10.1074/jbc.C000592200 . free .
• Russell ST, Hirai K, Tisdale MJ . Role of β3-adrenergic receptors in the action of a tumour lipid mobilizing factor . Br. J. Cancer . 86 . 3 . 424–8 . 2002 . 11875710 . 2375201 . 10.1038/sj.bjc.6600086 .

External links

• Web site: β₃-adrenoceptor . IUPHAR Database of Receptors and Ion Channels . International Union of Basic and Clinical Pharmacology . 25 November 2008 . 30 December 2014 . https://web.archive.org/web/20141230175443/http://www.iuphar-db.org/GPCR/ReceptorDisplayForward?receptorID=2191 . dead .

Notes and References

1. Web site: Entrez Gene: ADRB3 adrenergic, beta-3-, receptor.
2. Ferrer-Lorente R, Cabot C, Fernández-López JA, Alemany M . Combined effects of oleoyl-estrone and a β₃-adrenergic agonist (CL316,243) on lipid stores of diet-induced overweight male Wistar rats . Life Sciences . 77 . 16 . 2051–8 . September 2005 . 15935402 . 10.1016/j.lfs.2005.04.008 .
3. Book: Rang, H. P. . Pharmacology . Churchill Livingstone . Edinburgh . 2003 . 0-443-07145-4 . Page 163
4. Sawa M, Harada H . Recent Developments in the Design of Orally Bioavailable β3-Adrenergic Receptor Agonists . Current Medicinal Chemistry . 13 . 1 . 25–37 . 2006 . 16457637 . 10.2174/092986706775198006 .
5. Consoli D, Leggio GM, Mazzola C, Micale V, Drago F . Behavioral effects of the β₃ adrenoceptor agonist SR58611A: is it the putative prototype of a new class of antidepressant/anxiolytic drugs? . European Journal of Pharmacology . 573 . 1–3 . 139–47 . November 2007 . 17669397 . 10.1016/j.ejphar.2007.06.048 .
6. Overstreet DH, Stemmelin J, Griebel G . Confirmation of antidepressant potential of the selective β₃ adrenoceptor agonist amibegron in an animal model of depression . Pharmacology Biochemistry and Behavior . 89 . 4 . 623–6 . June 2008 . 18358519 . 10.1016/j.pbb.2008.02.020 . 35026036 .
7. Mukaida S, Sato M, Öberg AI, Dehvari N, Olsen JM, Kocan M, Halls ML, Merlin J, Sandström AL, Csikasz RI, Evans BA, Summers RJ, Hutchinson DS, Bengtsson T . 6 . BRL37344 stimulates GLUT4 translocation and glucose uptake in skeletal muscle via β2-adrenoceptors without causing classical receptor desensitization . American Journal of Physiology. Regulatory, Integrative and Comparative Physiology . 316 . 5 . R666–R677 . May 2019 . 30892909 . 10.1152/ajpregu.00285.2018 . free .
8. Fu L, Isobe K, Zeng Q, Suzukawa K, Takekoshi K, Kawakami Y . The effects of beta(3)-adrenoceptor agonist CL-316,243 on adiponectin, adiponectin receptors and tumor necrosis factor-alpha expressions in adipose tissues of obese diabetic KKAy mice . European Journal of Pharmacology . 584 . 1 . 202–6 . 2008 . 18304529 . 10.1016/j.ejphar.2008.01.028 .
9. Candelore MR, Deng L, Tota L, Guan XM, Amend A, Liu Y, Newbold R, Cascieri MA, Weber AE . Potent and selective human beta(3)-adrenergic receptor antagonists. . The Journal of Pharmacology and Experimental Therapeutics . 290 . 2 . 649–55 . Aug 1999 . 10411574 .
10. Larsen TM, Toubro S, van Baak MA, Gottesdiener KM, Larson P, Saris WH, Astrup A . Effect of a 28-d treatment with L-796568, a novel β₃-adrenergic receptor agonist, on energy expenditure and body composition in obese men . The American Journal of Clinical Nutrition . 76 . 4 . 780–8 . 2002 . 12324291 . 10.1093/ajcn/76.4.780. free .
11. Gras J . Mirabegron for the treatment of overactive bladder . Drugs of Today . 48 . 1 . 25–32 . 2012 . 22384458 . 10.1358/dot.2012.48.1.1738056 .
12. Rozec B, Erfanian M, Laurent K, Trochu JN, Gauthier C . Nebivolol, a vasodilating selective beta(1)-blocker, is a beta(3)-adrenoceptor agonist in the nonfailing transplanted human heart . J Am Coll Cardiol . 2009 . 53 . 17 . 1532–8 . 10.1016/j.jacc.2008.11.057 . 19389564 .
13. Hicks A, McCafferty GP, Riedel E, Aiyar N, Pullen M, Evans C, Luce TD, Coatney RW, Rivera GC, Westfall TD, Hieble JP . GW427353 (solabegron), a novel, selective beta3-adrenergic receptor agonist, evokes bladder relaxation and increases micturition reflex threshold in the dog . The Journal of Pharmacology and Experimental Therapeutics . 323 . 1 . 202–9 . October 2007 . 17626794 . 10.1124/jpet.107.125757 . 19281697 .
14. Edmondson SD, Zhu C, ((Kar N-F)), Di Salvo J, Nagabukuro H, Sacre-Salem B, Dingley, Berger R, Goble SD, Morriello G, Harper B, Moyes CR, ((Shen D-M)), Wang L, Ball R, Fitzmaurice A, Frenkl T, Gichuru LN, Ha S, Hurley AL, Jochnowitz N, Levorse D, Mistry S, Miller RR, Ormes J, Salituro GM, Sanfiz A, Stevenson AS, Villa K, Zamlynny B, Green S, Struthers M, Weber AE . Discovery of Vibegron: A Potent and Selective β3 Adrenergic Receptor Agonist for the Treatment of Overactive Bladder.. Journal of Medicinal Chemistry . 59 . 2 . 609–23 . January 2016 . 26709102 . 10.1021/acs.jmedchem.5b01372 .
15. Nisoli E, Tonello C, Landi M, Carruba MO . Functional studies of the first selective β₃-adrenergic receptor antagonist SR 59230A in rat brown adipocytes . Mol. Pharmacol. . 49 . 1 . 7–14 . 1996 . 8569714 .
16. Bexis S, Docherty JR . Role of α1- and β3-adrenoceptors in the modulation by SR59230A of the effects of MDMA on body temperature in the mouse . British Journal of Pharmacology . 158 . 1 . 259–66 . April 2009 . 19422394 . 2795232 . 10.1111/j.1476-5381.2009.00186.x .
17. Cao W, Luttrell LM, Medvedev AV, Pierce KL, Daniel KW, Dixon TM, Lefkowitz RJ, Collins S . Direct binding of activated c-Src to the beta 3-adrenergic receptor is required for MAP kinase activation . J. Biol. Chem. . 275 . 49 . 38131–4 . 2000 . 11013230 . 10.1074/jbc.C000592200 . free .