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Hormesis pp 95–108Cite as

The Devil is in the Dose: Complexity of Receptor Systems and Responses

Abstract

Through evolutionary history the primary mechanism by which the cells or tissues of most organisms sense their environment has been the heptahelical G protein–coupled receptor (GPCR). This prototypic receptive entity has its origins in the earliest forms of life and often comprises up to 5% of the genome of most unicellular and multicellular life forms. The GPCR system has adapted to perceive almost all forms of environmental entities, for example, photons, odorants, lipids, carbohydrates, peptides, and nucleic acids. The GPCR system has also likely adapted to the presence of exogenous compounds that may at some doses be deleterious but at lower levels may indeed possess beneficial actions. Therefore, with respect to the evolutionary pressure of diverse environments, it would be an extreme advantage for an organism to adapt multiple components of its primary receptive system to take advantage of any beneficial effects of agents present in harsh or damaging environments.

Keywords

  • Gprotein–coupled receptor
  • Dose response
  • Allosteric
  • Conformation
  • Environment
  • Flavor
  • Receptive

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References

  • Ali MS, Sayeski PP, Dirksen LB, et al. (1997) Dependence on the motif YIPP for the physical association of jak2 kinase with the intracellular carboxyl tail of the angiotensin II AT1 receptor. J Biol Chem 272: 23382–23388.

    CAS  CrossRef  PubMed  Google Scholar 

  • Angers S, Salahpour A, Bouvier M. (2002) Dimerization: an emerging concept for G protein–coupled receptor ontogeny and function. Annu Rev Pharmacol Toxicol 42: 409–435.

    CAS  CrossRef  PubMed  Google Scholar 

  • Arch JR (2004) Do low-affinity states of beta-adrenoceptors have roles in physiology and medicine? Br J Pharmacol. 143: 517–518.

    Google Scholar 

  • Baker JG (2005) Site of action of beta-ligands at the human beta1-adrenoceptor. J Pharmacol Exp Ther 13: 1163–1171.

    CrossRef  Google Scholar 

  • Berg KA, Maayani S, Goldfarb J, et al. (1998) Effector pathway–dependent relative efficacy at serotonin type 2a and 2c receptors: evidence for agonist-directed trafficking of receptor stimulus. Mol Pharmacol 54: 94–104.

    CAS  PubMed  Google Scholar 

  • Birdsall NJM, Hulme EC, Stockton JM (1983) Muscarinic receptor subclasses: allosteric interactions. Cold Spring Harb Symp Quant Biol 48: 53–56.

    CAS  PubMed  Google Scholar 

  • Birdsall NJM, Lazareno S (2005) Allosterism at muscarinic receptors: ligands and mechanisms. Mini-Rev Med Chem 5: 523–543.

    CAS  CrossRef  PubMed  Google Scholar 

  • Bockaert J, Marin P, Dumuis A, et al. (2003) The ‘magic tail’ of G protein–coupled receptors: an anchorage for functional protein networks. FEBS Lett 546: 65–72.

    CAS  CrossRef  PubMed  Google Scholar 

  • Brady AE, Limbird LE (2002) G protein–coupled receptor interacting proteins: emerging roles in localization and signal transduction. Cell Signal 14: 297–309.

    CAS  CrossRef  PubMed  Google Scholar 

  • Chadwick W, Magnus T, Martin B, et al. (2008) Targeting TNF-alpha receptors for neurotherapeutics. Trends Neurosci 31: 504–511.

    CAS  CrossRef  PubMed  Google Scholar 

  • Christopoulos A, Kenakin T (2002) G protein–coupled receptor allosterism and complexing. Pharmacol Rev 54: 323–374.

    CAS  CrossRef  PubMed  Google Scholar 

  • Christopoulos A, May LT, Avlani VA, et al. (2004) G-protein–coupled receptor allosterism: the promise and the problem(s). Biochem Soc Trans 32(Pt 5): 873–877.

    CAS  CrossRef  PubMed  Google Scholar 

  • Daaka Y, Luttrell LM, Lefkowitz RJ (1997) Switching of the coupling of the β2-adrenergic receptor to different G proteins by protein kinase A. Nature 390: 88–91.

    CAS  CrossRef  PubMed  Google Scholar 

  • DeLean A, Stadel JM, Lefkowitz RJ (1980) A ternary complex model explains the agonist-specific binding properties of the adenylate cyclase–coupled beta-adrenergic receptor. J Biol Chem 255: 7108–7117.

    CAS  Google Scholar 

  • Franco R, Ferre S, Agnati L, et al. (2000) Evidence for adenosine/dopamine receptor interactions: indications for heteromerization. Neuropsychopharmacology 23: S50–S59.

    CAS  CrossRef  PubMed  Google Scholar 

  • Fredriksson R, Schiöth HB (2005) The repertoire of G-protein–coupled receptors in fully sequenced genomes. Mol Pharmacol 67: 1414–1425.

    CAS  CrossRef  PubMed  Google Scholar 

  • George SR, Fan T, Xie Z, et al. (2000) Oligomerization of μ- and δ-opioid receptors. Generation of novel functional properties. J Biol Chem 275: 26128–26135.

    CAS  CrossRef  PubMed  Google Scholar 

  • Granneman JG (2001) The putative β4-adrenergic receptor is a novel state of the β1-adrenergic receptor. Am J Physiol Endocrinol Metab 280: E199–E202.

    CAS  PubMed  Google Scholar 

  • Guo W, Shi L, Filizola M, et al. (2005) Crosstalk in G protein–coupled receptors: changes at the transmembrane homodimer interface determine activation. Proc Natl Acad Sci USA 102: 17495–17500.

    CAS  CrossRef  PubMed  Google Scholar 

  • Holloway AC, Qian H, Pipolo L, et al. (2002) Side-chain substitutions within angiotensin II reveal different requirements for signaling, internalization, and phosphorylation of type 1a angiotensin receptors. Mol Pharmacol 61: 768–777.

    CAS  CrossRef  PubMed  Google Scholar 

  • Jones KA, Borowsky B, Tamm JA, et al. (1998) GABA(B) receptors function as a heteromeric assembly of the subunits GABA(B)R1 and GABA(B)R2. Nature 396: 674–679.

    CAS  CrossRef  PubMed  Google Scholar 

  • Jordan BA, Devi LA (1999) G-protein–coupled receptor heterodimerization modulates receptor function. Nature 399: 697–700.

    CAS  CrossRef  PubMed  Google Scholar 

  • Keith DE, Murray SR, Zaki PA, et al. (1996) Morphine activates opioid receptors without causing their rapid internalization. J Biol Chem 271: 19021–19024.

    CAS  CrossRef  PubMed  Google Scholar 

  • Kenakin T (2002) Drug efficacy at G protein–coupled receptors. Ann Rev Pharmacol Toxicol 42: 349–379.

    CAS  CrossRef  Google Scholar 

  • Kenakin T (2003) Ligand-selective receptor conformations revisited. The promise and the problem. Trends Pharmacol Sci 24: 346–354.

    CAS  CrossRef  PubMed  Google Scholar 

  • Kohout TA, Nicholas SL, Perry SJ, et al. (2004) Differential desensitization, receptor phosphorylation, β-arrestin recruitment and ERK1/2 activation by the two endogenous ligands for the CC chemokine receptor 7. J Biol Chem 279: 23214–23222.

    CAS  CrossRef  PubMed  Google Scholar 

  • Konkar AA (2000) Aryloxypropanolamine and catecholamine ligand interactions with the β1 adrenergic receptor: evidence for interaction with distinct conformations of β1-adrenergic receptors. J Pharmacol Exp Ther 294: 923–932.

    CAS  PubMed  Google Scholar 

  • Lazareno S (2004) Thiochrome enhances acetylcholine affinity at muscarinic M4 receptors: receptor subtype selectivity via cooperativity rather than affinity. Mol Pharmacol 65: 257–266.

    CAS  CrossRef  PubMed  Google Scholar 

  • Laporte SA, Oakley RH, Zhang J, et al. (1999) The beta2-adrenergic receptor/beta arrestin complex recruits the clathrin adaptor AP-2 during endocytosis. Proc Natl Acad Sci USA 96: 3712–3717.

    CAS  CrossRef  PubMed  Google Scholar 

  • Liang Y, Fotiadis D, Filipek S, et al. (2003) Organization of the G protein–coupled receptors rhodopsin and opsin in native membranes. J Biol Chem 278: 21655–21662.

    CAS  CrossRef  PubMed  Google Scholar 

  • Lowe MD (2002) Comparison of the affinity of β-blockers for the two states of the β1-adrenoceptor in ferret ventricular myocardium. Br J Pharmacol 135: 451–461.

    CAS  CrossRef  PubMed  Google Scholar 

  • Luttrell LM, Ferguson SSG, Daaka Y et al. (1999) □-Arrestin–dependent formation of β2 adrenergic receptor/src protein kinase complexes. Science 283: 655–661.

    CAS  CrossRef  PubMed  Google Scholar 

  • Marlo JE, Niswender CM, Days EL, et al. 2008 Discovery and characterization of novel allosteric potentiators of M1 muscarinic receptors reveals multiple modes of activity. Mol Pharmacol Dec 1 [Epub ahead of print].

    Google Scholar 

  • Maudsley S, Gent JP, Findlay JB, et al. (1998) The relationship between the agonist-induced activation and desensitization of the human tachykinin NK2 receptor expressed in Xenopus oocytes. Br J Pharmacol 124: 675–684.

    CAS  CrossRef  PubMed  Google Scholar 

  • Maudsley S, Pierce KL, Zamah AM, et al. (2000) The beta(2)-adrenergic receptor mediates extracellular signal-regulated kinase activation via assembly of a multi-receptor complex with the epidermal growth factor receptor. J Biol Chem 275: 9572–9580.

    CAS  CrossRef  PubMed  Google Scholar 

  • Maudsley S, Zamah AM, Rahman N, Blitzer JT, Luttrell LM, Lefkowitz RJ, Hall RA (2000a) Platelet-derived growth factor receptor association with Na(+)/H(+) exchanger regulatory factor potentiates receptor activity. Mol Cell Biol 20: 8352–8363.

    CAS  CrossRef  PubMed  Google Scholar 

  • Maudsley S, Davidson L, Pawson AJ, et al. (2004) Gonadotropin-releasing hormone (GnRH) antagonists promote proapoptotic signaling in peripheral reproductive tumor cells by activating a galphai-coupling state of the type I GnRH receptor. Cancer Res 64: 7533–7544.

    CAS  CrossRef  PubMed  Google Scholar 

  • Maudsley S, Martin B, Luttrell LM (2005) The origins of diversity and specicity in G protein coupled receptor signaling. J Pharmacol Exp Ther 314: 485–494.

    CAS  CrossRef  PubMed  Google Scholar 

  • Maudsley S, Martin B, Luttrell LM (2007b) G protein–coupled receptor signaling complexity in neuronal tissue: implications for novel therapeutics. Curr Alzheimer Res 4: 3–19.

    CAS  CrossRef  PubMed  Google Scholar 

  • Maudsley S, Naor Z, Bonfil D, et al. (2007a) Proline-rich tyrosine kinase 2 mediates gonadotropin-releasing hormone signaling to a specific extracellularly regulated kinase-sensitive transcriptional locus in the luteinizing hormone beta-subunit gene. Mol Endocrinol 21: 1216–1233.

    CAS  CrossRef  PubMed  Google Scholar 

  • May LT, Leach K, Sexton PA, et al. (2007) Allosteric modulation of g protein–coupled receptors ann. Rev Pharmacol Toxicol 47: 1–51.

    CAS  CrossRef  Google Scholar 

  • Moolenaar P (2003) The ‘state’ of β-adrenoceptors. Br J Pharmacol 140: 1–2.

    CrossRef  Google Scholar 

  • Pak MD, Fishman PH (1996) Anomalous behavior of CGP 12177a on β1-adrenergic receptors. J Recept Signal Transduct Res 16: 1–23.

    CrossRef  PubMed  Google Scholar 

  • Peroutka SJ, Snyder SH (1980) Regulation of serotonin2 (5-HT2) receptors labeled with [3H]spiroperidol by chronic treatment with the antidepressant amitriptyline. J Pharmacol Exp Ther 215: 582–587.

    CAS  PubMed  Google Scholar 

  • Pommier B, Da Nascimento S, Dumont S, et al. (1999) The cholecystokinin B receptor is coupled to two effector pathways through pertussis toxin–sensitive and –insensitive G proteins. J Neurochem 73: 281–288.

    CAS  CrossRef  PubMed  Google Scholar 

  • Rimoldi V, Reversi A, Taverna E, et al. (2003) Oxytocin receptor elicits different EGFR/MAPK activation patterns depending on its localization in caveolin-1 enriched domains. Oncogene 22: 6054–6060.

    CAS  CrossRef  PubMed  Google Scholar 

  • Roettger BF, Ghanekar D, Rao R, Toledo C, Yingling J, Pinon D,, Miller LJ (1997) Antagonist-stimulated internalization of the G protein–coupled cholecystokinin receptor. Mol Pharmacol 51: 357–362.

    CAS  PubMed  Google Scholar 

  • Sagan S, Karoyan P, Chassaing G, et al. (1996) Tachykinin peptides affect differently the second messenger pathways after binding to CHO-expressed human NK-1 receptors. J Pharmacol Exp Ther 276: 1039–1048.

    CAS  PubMed  Google Scholar 

  • Samama P, Cotecchia S, Costa T, et al. (1993) A mutation-induced activated state of the beta 2-adrenergic receptor. Extending the ternary complex model. J Biol Chem 268: 4625–4636.

    CAS  PubMed  Google Scholar 

  • Sexton PM, Albiston A, Morfis M, et al. (2001) Receptor activity modifying proteins. Cell Signal 13: 73–83.

    CAS  CrossRef  PubMed  Google Scholar 

  • Sneddon WB, Syme CA, Bisello A, et al. (2003) Activation-independent parathyroid hormone receptor internalization is regulated by NHERF1 (EBP50). J Biol Chem 278: 43787–43796.

    CAS  CrossRef  PubMed  Google Scholar 

  • Soudijn W (2004) Allosteric modulation of G protein–coupled receptors: perspective and recent developments. Drug Discov Today 9: 752–758.

    CAS  CrossRef  PubMed  Google Scholar 

  • Stout BD, Clarke WP (2002) Berg KA rapid desensitization of the serotonin(2c) receptor system: effector pathway and agonist dependence. J Pharmacol Exp Ther 302: 957–962.

    CAS  CrossRef  PubMed  Google Scholar 

  • Takeda S, Kadowaki S, Haga T, et al. (2002) Identification of G protein–coupled receptor genes from the human genome sequence. FEBS Lett 520: 97–101.

    CAS  CrossRef  PubMed  Google Scholar 

  • Tang Y, Hu LA, Miller WE, et al. (1999) Identification of the endophilins (SH3p4/p8/p13) as novel binding partners for the beta1-adrenergic receptor. Proc Natl Acad Sci USA 96: 12559–12564.

    CAS  CrossRef  PubMed  Google Scholar 

  • Urban JD, Clarke WP, von Zastrow M, et al. (2007) Functional selectivity and classical concepts of quantitative pharmacology. J Pharmacol Exp Ther 320: 1–13.

    CAS  CrossRef  PubMed  Google Scholar 

  • van Hooft JA, Vijverberg HP (1996) Selection of distinct conformational states of the 5-HT3 receptor by full and partial agonists. Br J Pharmacol 117: 839–846.

    PubMed  Google Scholar 

  • Waelbroeck M (1994) Identification of drugs competing with d-tubocurarine for an allosteric site on cardiac muscarinic receptors. Mol Pharmacol 46: 685–692.

    CAS  PubMed  Google Scholar 

  • Wang Q, Zhao J, Brady AE et al (2004) Spinophilin blocks arrestin actions in vitro and in vivo at G protein–coupled receptors. Science 304: 1940–1944.

    CAS  CrossRef  PubMed  Google Scholar 

  • Watson C (2005) The CCR5 receptor–based mechanism of action of 873140, a potent allosteric non competitive HIV entry inhibitor. Mol Pharmacol 67: 1268–1282.

    CAS  CrossRef  PubMed  Google Scholar 

  • Yu Y, Zhang L, Yin X, et al. (1996) μ-Opioid receptor phosphorylation, desensitization and ligand efficacy. J Biol Chem 272: 28869–28874.

    CrossRef  Google Scholar 

  • Zhang SJ, Cheng H, Zhou YY, et al. (2000) Inhibition of spontaneous beta 2-adrenergic activation rescues beta 1-adrenergic contractile response in cardiomyocytes overexpressing beta 2-adrenoceptor. J Biol Chem 275: 21773–21779.

    CAS  CrossRef  PubMed  Google Scholar 

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Chadwick, W., Maudsley, S. (2010). The Devil is in the Dose: Complexity of Receptor Systems and Responses. In: Mattson, M., Calabrese, E. (eds) Hormesis. Humana Press. https://doi.org/10.1007/978-1-60761-495-1_5

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