Structure, function, and regulation of adrenergic receptors.
PDF (4.0M)
Journal: 1993/October - Protein Science
ISSN: 0961-8368
Abstract:
Adrenergic receptors for adrenaline and noradrenaline belong to the large multigenic family of receptors coupled to GTP-binding proteins. Three pharmacologic types have been identified: alpha 1-, alpha 2-, and beta-adrenergic receptors. Each of these has three subtypes, characterized by both structural and functional differences. The alpha 2 and beta receptors are coupled negatively and positively, respectively, to adenylyl cyclase via Gi or Gs regulatory proteins, and the alpha 1 receptors modulate phospholipase C via the Go protein. Subtype expression is regulated at the level of the gene, the mRNA, and the protein through various transcriptional and postsynthetic mechanisms. Adrenergic receptors constitute, after rhodopsin, one of the best studied models for the other receptors coupled to G proteins that are likely to display similar structural and functional properties.
Open in
PUBMED | PMC | DOI | Google Scholar | Wikipedia
Relations:
Content
Citations
(31)
References
(68)
Chemicals
(1)
Organisms
(2)
Processes
(4)
Anatomy
(1)
Similar articles
Articles by the same authors
Discussion board
Protein Sci 2(8): 1198-1209
PMID: 8401205

Structure, function, and regulation of adrenergic receptors.

Abstract

Adrenergic receptors for adrenaline and noradrenaline belong to the large multigenic family of receptors coupled to GTP-binding proteins. Three pharmacologic types have been identified: alpha 1-, alpha 2-, and beta-adrenergic receptors. Each of these has three subtypes, characterized by both structural and functional differences. The alpha 2 and beta receptors are coupled negatively and positively, respectively, to adenylyl cyclase via Gi or Gs regulatory proteins, and the alpha 1 receptors modulate phospholipase C via the Go protein. Subtype expression is regulated at the level of the gene, the mRNA, and the protein through various transcriptional and postsynthetic mechanisms. Adrenergic receptors constitute, after rhodopsin, one of the best studied models for the other receptors coupled to G proteins that are likely to display similar structural and functional properties.

Full Text

The Full Text of this article is available as a PDF (4.0M).

Selected References

These references are in PubMed. This may not be the complete list of references from this article.
  • Allen LF, Lefkowitz RJ, Caron MG, Cotecchia S. G-protein-coupled receptor genes as protooncogenes: constitutively activating mutation of the alpha 1B-adrenergic receptor enhances mitogenesis and tumorigenicity. Proc Natl Acad Sci U S A. 1991 Dec 15;88(24):11354–11358.[PMC free article] [PubMed] [Google Scholar]
  • Benovic JL, Mayor F, Jr, Staniszewski C, Lefkowitz RJ, Caron MG. Purification and characterization of the beta-adrenergic receptor kinase. J Biol Chem. 1987 Jul 5;262(19):9026–9032. [PubMed] [Google Scholar]
  • Bouvier M, Collins S, O'Dowd BF, Campbell PT, de Blasi A, Kobilka BK, MacGregor C, Irons GP, Caron MG, Lefkowitz RJ. Two distinct pathways for cAMP-mediated down-regulation of the beta 2-adrenergic receptor. Phosphorylation of the receptor and regulation of its mRNA level. J Biol Chem. 1989 Oct 5;264(28):16786–16792. [PubMed] [Google Scholar]
  • Bouvier M, Hausdorff WP, De Blasi A, O'Dowd BF, Kobilka BK, Caron MG, Lefkowitz RJ. Removal of phosphorylation sites from the beta 2-adrenergic receptor delays onset of agonist-promoted desensitization. Nature. 1988 May 26;333(6171):370–373. [PubMed] [Google Scholar]
  • Breyer RM, Strosberg AD, Guillet JG. Mutational analysis of ligand binding activity of beta 2 adrenergic receptor expressed in Escherichia coli. EMBO J. 1990 Sep;9(9):2679–2684.[PMC free article] [PubMed] [Google Scholar]
  • Bruno JF, Whittaker J, Song JF, Berelowitz M. Molecular cloning and sequencing of a cDNA encoding a human alpha 1A adrenergic receptor. Biochem Biophys Res Commun. 1991 Sep 30;179(3):1485–1490. [PubMed] [Google Scholar]
  • Bylund DB, Blaxall HS, Iversen LJ, Caron MG, Lefkowitz RJ, Lomasney JW. Pharmacological characteristics of alpha 2-adrenergic receptors: comparison of pharmacologically defined subtypes with subtypes identified by molecular cloning. Mol Pharmacol. 1992 Jul;42(1):1–5. [PubMed] [Google Scholar]
  • Caron MG, Srinivasan Y, Pitha J, Kociolek K, Lefkowitz RJ. Affinity chromatography of the beta-adrenergic receptor. J Biol Chem. 1979 Apr 25;254(8):2923–2927. [PubMed] [Google Scholar]
  • Cervantes-Olivier P, Delavier-Klutchko C, Durieu-Trautmann O, Kaveri S, Desmandril M, Strosberg AD. The beta 2-adrenergic receptors of human epidermoid carcinoma cells bear two different types of oligosaccharides which influence expression on the cell surface. Biochem J. 1988 Feb 15;250(1):133–143.[PMC free article] [PubMed] [Google Scholar]
  • Cervantes-Olivier P, Durieu-Trautmann O, Delavier-Klutchko C, Strosberg AD. The oligosaccharide moiety of the beta 1-adrenergic receptor from turkey erythrocytes has a biantennary, N-acetyllactosamine-containing structure. Biochemistry. 1985 Jul 2;24(14):3765–3770. [PubMed] [Google Scholar]
  • Collins S, Altschmied J, Herbsman O, Caron MG, Mellon PL, Lefkowitz RJ. A cAMP response element in the beta 2-adrenergic receptor gene confers transcriptional autoregulation by cAMP. J Biol Chem. 1990 Nov 5;265(31):19330–19335. [PubMed] [Google Scholar]
  • Collins S, Caron MG, Lefkowitz RJ. Regulation of adrenergic receptor responsiveness through modulation of receptor gene expression. Annu Rev Physiol. 1991;53:497–508. [PubMed] [Google Scholar]
  • Cotecchia S, Exum S, Caron MG, Lefkowitz RJ. Regions of the alpha 1-adrenergic receptor involved in coupling to phosphatidylinositol hydrolysis and enhanced sensitivity of biological function. Proc Natl Acad Sci U S A. 1990 Apr;87(8):2896–2900.[PMC free article] [PubMed] [Google Scholar]
  • Cotecchia S, Ostrowski J, Kjelsberg MA, Caron MG, Lefkowitz RJ. Discrete amino acid sequences of the alpha 1-adrenergic receptor determine the selectivity of coupling to phosphatidylinositol hydrolysis. J Biol Chem. 1992 Jan 25;267(3):1633–1639. [PubMed] [Google Scholar]
  • Diamond MI, Miner JN, Yoshinaga SK, Yamamoto KR. Transcription factor interactions: selectors of positive or negative regulation from a single DNA element. Science. 1990 Sep 14;249(4974):1266–1272. [PubMed] [Google Scholar]
  • Dixon RA, Kobilka BK, Strader DJ, Benovic JL, Dohlman HG, Frielle T, Bolanowski MA, Bennett CD, Rands E, Diehl RE, et al. Cloning of the gene and cDNA for mammalian beta-adrenergic receptor and homology with rhodopsin. Nature. 1986 May 1;321(6065):75–79. [PubMed] [Google Scholar]
  • Dixon RA, Sigal IS, Candelore MR, Register RB, Scattergood W, Rands E, Strader CD. Structural features required for ligand binding to the beta-adrenergic receptor. EMBO J. 1987 Nov;6(11):3269–3275.[PMC free article] [PubMed] [Google Scholar]
  • Dixon RA, Sigal IS, Strader CD. Structure-function analysis of the beta-adrenergic receptor. Cold Spring Harb Symp Quant Biol. 1988;53(Pt 1):487–497. [PubMed] [Google Scholar]
  • Dohlman HG, Caron MG, DeBlasi A, Frielle T, Lefkowitz RJ. Role of extracellular disulfide-bonded cysteines in the ligand binding function of the beta 2-adrenergic receptor. Biochemistry. 1990 Mar 6;29(9):2335–2342. [PubMed] [Google Scholar]
  • Dohlman HG, Thorner J, Caron MG, Lefkowitz RJ. Model systems for the study of seven-transmembrane-segment receptors. Annu Rev Biochem. 1991;60:653–688. [PubMed] [Google Scholar]
  • Emorine LJ, Feve B, Pairault J, Briend-Sutren MM, Marullo S, Delavier-Klutchko C, Strosberg DA. Structural basis for functional diversity of beta 1-, beta 2- and beta 3-adrenergic receptors. Biochem Pharmacol. 41(6-7):853–859. [PubMed] [Google Scholar]
  • 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. 1989 Sep 8;245(4922):1118–1121. [PubMed] [Google Scholar]
  • Emorine LJ, Marullo S, Delavier-Klutchko C, Kaveri SV, Durieu-Trautmann O, Strosberg AD. Structure of the gene for human beta 2-adrenergic receptor: expression and promoter characterization. Proc Natl Acad Sci U S A. 1987 Oct;84(20):6995–6999.[PMC free article] [PubMed] [Google Scholar]
  • Fève B, Baude B, Krief S, Strosberg AD, Pairault J, Emorine LJ. Inhibition by dexamethasone of beta 3-adrenergic receptor responsiveness in 3T3-F442A adipocytes. Evidence for a transcriptional mechanism. J Biol Chem. 1992 Aug 5;267(22):15909–15915. [PubMed] [Google Scholar]
  • Fraser CM, Chung FZ, Wang CD, Venter JC. Site-directed mutagenesis of human beta-adrenergic receptors: substitution of aspartic acid-130 by asparagine produces a receptor with high-affinity agonist binding that is uncoupled from adenylate cyclase. Proc Natl Acad Sci U S A. 1988 Aug;85(15):5478–5482.[PMC free article] [PubMed] [Google Scholar]
  • Frielle T, Collins S, Daniel KW, Caron MG, Lefkowitz RJ, Kobilka BK. Cloning of the cDNA for the human beta 1-adrenergic receptor. Proc Natl Acad Sci U S A. 1987 Nov;84(22):7920–7924.[PMC free article] [PubMed] [Google Scholar]
  • Guyer CA, Horstman DA, Wilson AL, Clark JD, Cragoe EJ, Jr, Limbird LE. Cloning, sequencing, and expression of the gene encoding the porcine alpha 2-adrenergic receptor. Allosteric modulation by Na+, H+, and amiloride analogs. J Biol Chem. 1990 Oct 5;265(28):17307–17317. [PubMed] [Google Scholar]
  • Hadcock JR, Port JD, Gelman MS, Malbon CC. Cross-talk between tyrosine kinase and G-protein-linked receptors. Phosphorylation of beta 2-adrenergic receptors in response to insulin. J Biol Chem. 1992 Dec 25;267(36):26017–26022. [PubMed] [Google Scholar]
  • Hadcock JR, Ros M, Malbon CC. Agonist regulation of beta-adrenergic receptor mRNA. Analysis in S49 mouse lymphoma mutants. J Biol Chem. 1989 Aug 15;264(23):13956–13961. [PubMed] [Google Scholar]
  • Hausdorff WP, Bouvier M, O'Dowd BF, Irons GP, Caron MG, Lefkowitz RJ. Phosphorylation sites on two domains of the beta 2-adrenergic receptor are involved in distinct pathways of receptor desensitization. J Biol Chem. 1989 Jul 25;264(21):12657–12665. [PubMed] [Google Scholar]
  • Henderson R, Baldwin JM, Ceska TA, Zemlin F, Beckmann E, Downing KH. Model for the structure of bacteriorhodopsin based on high-resolution electron cryo-microscopy. J Mol Biol. 1990 Jun 20;213(4):899–929. [PubMed] [Google Scholar]
  • Kobilka BK, Dixon RA, Frielle T, Dohlman HG, Bolanowski MA, Sigal IS, Yang-Feng TL, Francke U, Caron MG, Lefkowitz RJ. cDNA for the human beta 2-adrenergic receptor: a protein with multiple membrane-spanning domains and encoded by a gene whose chromosomal location is shared with that of the receptor for platelet-derived growth factor. Proc Natl Acad Sci U S A. 1987 Jan;84(1):46–50.[PMC free article] [PubMed] [Google Scholar]
  • Kobilka BK, Kobilka TS, Daniel K, Regan JW, Caron MG, Lefkowitz RJ. Chimeric alpha 2-,beta 2-adrenergic receptors: delineation of domains involved in effector coupling and ligand binding specificity. Science. 1988 Jun 3;240(4857):1310–1316. [PubMed] [Google Scholar]
  • Kobilka BK, Matsui H, Kobilka TS, Yang-Feng TL, Francke U, Caron MG, Lefkowitz RJ, Regan JW. Cloning, sequencing, and expression of the gene coding for the human platelet alpha 2-adrenergic receptor. Science. 1987 Oct 30;238(4827):650–656. [PubMed] [Google Scholar]
  • 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. 1993 Jan;91(1):344–349.[PMC free article] [PubMed] [Google Scholar]
  • Lands AM, Arnold A, McAuliff JP, Luduena FP, Brown TG., Jr Differentiation of receptor systems activated by sympathomimetic amines. Nature. 1967 May 6;214(5088):597–598. [PubMed] [Google Scholar]
  • Lohse MJ, Benovic JL, Codina J, Caron MG, Lefkowitz RJ. beta-Arrestin: a protein that regulates beta-adrenergic receptor function. Science. 1990 Jun 22;248(4962):1547–1550. [PubMed] [Google Scholar]
  • Lohse MJ, Lefkowitz RJ, Caron MG, Benovic JL. Inhibition of beta-adrenergic receptor kinase prevents rapid homologous desensitization of beta 2-adrenergic receptors. Proc Natl Acad Sci U S A. 1989 May;86(9):3011–3015.[PMC free article] [PubMed] [Google Scholar]
  • Lomasney JW, Lorenz W, Allen LF, King K, Regan JW, Yang-Feng TL, Caron MG, Lefkowitz RJ. Expansion of the alpha 2-adrenergic receptor family: cloning and characterization of a human alpha 2-adrenergic receptor subtype, the gene for which is located on chromosome 2. Proc Natl Acad Sci U S A. 1990 Jul;87(13):5094–5098.[PMC free article] [PubMed] [Google Scholar]
  • Marullo S, Emorine LJ, Strosberg AD, Delavier-Klutchko C. Selective binding of ligands to beta 1, beta 2 or chimeric beta 1/beta 2-adrenergic receptors involves multiple subsites. EMBO J. 1990 May;9(5):1471–1476.[PMC free article] [PubMed] [Google Scholar]
  • Moffett S, Mouillac B, Bonin H, Bouvier M. Altered phosphorylation and desensitization patterns of a human beta 2-adrenergic receptor lacking the palmitoylated Cys341. EMBO J. 1993 Jan;12(1):349–356.[PMC free article] [PubMed] [Google Scholar]
  • Mouillac B, Caron M, Bonin H, Dennis M, Bouvier M. Agonist-modulated palmitoylation of beta 2-adrenergic receptor in Sf9 cells. J Biol Chem. 1992 Oct 25;267(30):21733–21737. [PubMed] [Google Scholar]
  • Nantel F, Bonin H, Emorine LJ, Zilberfarb V, Strosberg AD, Bouvier M, Marullo S. The human beta 3-adrenergic receptor is resistant to short term agonist-promoted desensitization. Mol Pharmacol. 1993 Apr;43(4):548–555. [PubMed] [Google Scholar]
  • O'Dowd BF, Hnatowich M, Caron MG, Lefkowitz RJ, Bouvier M. Palmitoylation of the human beta 2-adrenergic receptor. Mutation of Cys341 in the carboxyl tail leads to an uncoupled nonpalmitoylated form of the receptor. J Biol Chem. 1989 May 5;264(13):7564–7569. [PubMed] [Google Scholar]
  • Okamoto T, Murayama Y, Hayashi Y, Inagaki M, Ogata E, Nishimoto I. Identification of a Gs activator region of the beta 2-adrenergic receptor that is autoregulated via protein kinase A-dependent phosphorylation. Cell. 1991 Nov 15;67(4):723–730. [PubMed] [Google Scholar]
  • Ostrowski J, Kjelsberg MA, Caron MG, Lefkowitz RJ. Mutagenesis of the beta 2-adrenergic receptor: how structure elucidates function. Annu Rev Pharmacol Toxicol. 1992;32:167–183. [PubMed] [Google Scholar]
  • Port JD, Huang LY, Malbon CC. Beta-adrenergic agonists that down-regulate receptor mRNA up-regulate a M(r) 35,000 protein(s) that selectively binds to beta-adrenergic receptor mRNAs. J Biol Chem. 1992 Nov 25;267(33):24103–24108. [PubMed] [Google Scholar]
  • Ramarao CS, Denker JM, Perez DM, Gaivin RJ, Riek RP, Graham RM. Genomic organization and expression of the human alpha 1B-adrenergic receptor. J Biol Chem. 1992 Oct 25;267(30):21936–21945. [PubMed] [Google Scholar]
  • Rubenstein RC, Wong SK, Ross EM. The hydrophobic tryptic core of the beta-adrenergic receptor retains Gs regulatory activity in response to agonists and thiols. J Biol Chem. 1987 Dec 5;262(34):16655–16662. [PubMed] [Google Scholar]
  • Samama P, Cotecchia S, Costa T, Lefkowitz RJ. A mutation-induced activated state of the beta 2-adrenergic receptor. Extending the ternary complex model. J Biol Chem. 1993 Mar 5;268(7):4625–4636. [PubMed] [Google Scholar]
  • Schwinn DA, Lomasney JW, Lorenz W, Szklut PJ, Fremeau RT, Jr, Yang-Feng TL, Caron MG, Lefkowitz RJ, Cotecchia S. Molecular cloning and expression of the cDNA for a novel alpha 1-adrenergic receptor subtype. J Biol Chem. 1990 May 15;265(14):8183–8189. [PubMed] [Google Scholar]
  • Strader CD, Candelore MR, Hill WS, Sigal IS, Dixon RA. Identification of two serine residues involved in agonist activation of the beta-adrenergic receptor. J Biol Chem. 1989 Aug 15;264(23):13572–13578. [PubMed] [Google Scholar]
  • Strader CD, Candelore MR, Hill WS, Dixon RA, Sigal IS. A single amino acid substitution in the beta-adrenergic receptor promotes partial agonist activity from antagonists. J Biol Chem. 1989 Oct 5;264(28):16470–16477. [PubMed] [Google Scholar]
  • Strader CD, Dixon RA, Cheung AH, Candelore MR, Blake AD, Sigal IS. Mutations that uncouple the beta-adrenergic receptor from Gs and increase agonist affinity. J Biol Chem. 1987 Dec 5;262(34):16439–16443. [PubMed] [Google Scholar]
  • Strader CD, Gaffney T, Sugg EE, Candelore MR, Keys R, Patchett AA, Dixon RA. Allele-specific activation of genetically engineered receptors. J Biol Chem. 1991 Jan 5;266(1):5–8. [PubMed] [Google Scholar]
  • Strader CD, Sigal IS, Blake AD, Cheung AH, Register RB, Rands E, Zemcik BA, Candelore MR, Dixon RA. The carboxyl terminus of the hamster beta-adrenergic receptor expressed in mouse L cells is not required for receptor sequestration. Cell. 1987 Jun 19;49(6):855–863. [PubMed] [Google Scholar]
  • Strosberg AD. Structure/function relationship of proteins belonging to the family of receptors coupled to GTP-binding proteins. Eur J Biochem. 1991 Feb 26;196(1):1–10. [PubMed] [Google Scholar]
  • Strosberg AD. Biotechnology of beta-adrenergic receptors. Mol Neurobiol. 1990 Fall-Winter;4(3-4):211–250. [PubMed] [Google Scholar]
  • Strosberg AD, Camoin L, Blin N, Maigret B. In receptors coupled to GTP-binding proteins, ligand binding and G-protein activation is a multistep dynamic process. Drug Des Discov. 1993;9(3-4):199–211. [PubMed] [Google Scholar]
  • Strosberg AD, Marullo S. Functional expression of receptors in microorganisms. Trends Pharmacol Sci. 1992 Mar;13(3):95–98. [PubMed] [Google Scholar]
  • Surprenant A, Horstman DA, Akbarali H, Limbird LE. A point mutation of the alpha 2-adrenoceptor that blocks coupling to potassium but not calcium currents. Science. 1992 Aug 14;257(5072):977–980. [PubMed] [Google Scholar]
  • Suryanarayana S, Daunt DA, Von Zastrow M, Kobilka BK. A point mutation in the seventh hydrophobic domain of the alpha 2 adrenergic receptor increases its affinity for a family of beta receptor antagonists. J Biol Chem. 1991 Aug 15;266(23):15488–15492. [PubMed] [Google Scholar]
  • Thomas RF, Holt BD, Schwinn DA, Liggett SB. Long-term agonist exposure induces upregulation of beta 3-adrenergic receptor expression via multiple cAMP response elements. Proc Natl Acad Sci U S A. 1992 May 15;89(10):4490–4494.[PMC free article] [PubMed] [Google Scholar]
  • Tota MR, Strader CD. Characterization of the binding domain of the beta-adrenergic receptor with the fluorescent antagonist carazolol. Evidence for a buried ligand binding site. J Biol Chem. 1990 Oct 5;265(28):16891–16897. [PubMed] [Google Scholar]
  • Vauquelin G, Bottari S, Kanarek L, Strosberg AD. Evidence for essential disulfide bonds in beta1-adrenergic receptors of turkey erythrocyte membranes. Inactivation by dithiothreitol. J Biol Chem. 1979 Jun 10;254(11):4462–4469. [PubMed] [Google Scholar]
  • Vauquelin G, Geynet P, Hanoune J, Strosberg AD. Affinity chromatography of the beta-adrenergic receptor from turkey erythrocytes. Eur J Biochem. 1979 Aug 1;98(2):543–556. [PubMed] [Google Scholar]
  • Wong SK, Slaughter C, Ruoho AE, Ross EM. The catecholamine binding site of the beta-adrenergic receptor is formed by juxtaposed membrane-spanning domains. J Biol Chem. 1988 Jun 15;263(17):7925–7928. [PubMed] [Google Scholar]
  • Yarden Y, Rodriguez H, Wong SK, Brandt DR, May DC, Burnier J, Harkins RN, Chen EY, Ramachandran J, Ullrich A, et al. The avian beta-adrenergic receptor: primary structure and membrane topology. Proc Natl Acad Sci U S A. 1986 Sep;83(18):6795–6799.[PMC free article] [PubMed] [Google Scholar]
Laboratoire d'Immuno-Pharmacologie Moléculaire, Institut Cochin de Génétique Moléculaire, Paris, France.
Laboratoire d'Immuno-Pharmacologie Moléculaire, Institut Cochin de Génétique Moléculaire, Paris, France.
Copyright notice

Abstract

Adrenergic receptors for adrenaline and noradrenaline belong to the large multigenic family of receptors coupled to GTP-binding proteins. Three pharmacologic types have been identified: alpha 1-, alpha 2-, and beta-adrenergic receptors. Each of these has three subtypes, characterized by both structural and functional differences. The alpha 2 and beta receptors are coupled negatively and positively, respectively, to adenylyl cyclase via Gi or Gs regulatory proteins, and the alpha 1 receptors modulate phospholipase C via the Go protein. Subtype expression is regulated at the level of the gene, the mRNA, and the protein through various transcriptional and postsynthetic mechanisms. Adrenergic receptors constitute, after rhodopsin, one of the best studied models for the other receptors coupled to G proteins that are likely to display similar structural and functional properties.

Abstract
Full Text
Selected References
Collaboration tool especially designed for Life Science professionals.Drag-and-drop any entity to your messages.