The AAPS Journal

, Volume 7, Issue 4, pp E871–E884 | Cite as

Hallucinogen actions on 5-HT receptors reveal distinct mechanisms of activation and signaling by G protein-coupled receptors



We review the effect of some key advances in the characterization of molecular mechanisms of signaling by G protein-coupled receptors (GPCRs) on our current understanding of mechanisms of drugs of abuse. These advances are illustrated by results from our ongoing work on the actions of hallucinogens on serotonin (5-HT) receptors. We show how a combined computational and experimental approach can reveal specific modes of receptor activation underlying the difference in properties of hallucinogens compared with nonhallucinogenic congeners. These modes of activation—that can produce distinct ligand-dependent receptor states—are identified in terms of structural motifs (SM) in molecular models of the receptors, which were shown to constitute conserved functional microdomains (FM). The role of several SM/FMs in the activation mechanism of the GPCRs is presented in detail to illustrate how this mechanism can lead to ligand-dependent modes of signaling by the receptors. Novel bioinformatics tools are described that were designed to support the quantitative mathematical modeling of ligand-specific signaling pathways activated by the 5-HT receptors targeted by hallucinogens. The approaches for mathematical modeling of signaling pathways activated by 5-HT receptors are described briefly in the context of ongoing work on detailed biochemical models of 5-HT2A, and combined 5-HT2A/5-HT1A, receptor-mediated activation of the MAPK 1,2 pathway. The continuing need for increasingly more realistic representation of signaling in dynamic compartments within the cell, endowed with spatio-temporal characteristics obtained from experiment, is emphasized. Such developments are essential for attaining a quantitative understanding of how the multiple functions of a cell are coordinated and regulated, and to evaluate the specifics of the perturbations caused by the drugs of abuse that target GPCRs.


molecular modeling molecular dynamics simulations membrane proteins signaling mathematical modeling bioinformatics tools 


  1. 1.
    Nichols DE. Hallucinogens.Pharmacol Ther 2004;101:131–181.PubMedCrossRefGoogle Scholar
  2. 2.
    Gresch PJ, Strickland LV, Sanders-Bush E. Lysergic acid diethylamide-induced Fos expression in rat brain: role of serotonin-2A receptors.Neuroscience. 2002;114:707–713.PubMedCrossRefGoogle Scholar
  3. 3.
    Aghajanian GK, Marek GJ. Serotonin and hallucinogens.Neuropsychopharmacology. 1999;21:16S-23S.PubMedGoogle Scholar
  4. 4.
    Visiers I, Ballesteros JA, Weinstein H. Three-dimensional representations of G protein-coupled receptor structures and mechanisms.Methods Enzymol. 2002;343:329–371.PubMedCrossRefGoogle Scholar
  5. 5.
    Filizola M, Visiers I, Skrabanek L, Campagne F, Weinstein H.Functional mechanisms of GPCRs in a structural context. In: Schousboe A, Bräumer-Osborne H, eds.Strategies in Molecular Neuropharmacology Totowa, NJ: Humana Press; 2003;235–266.Google Scholar
  6. 6.
    Filizola M, Weinstein H. The study of G-protein coupled receptor oligomerization with computational modeling and bioinformatics.FEBS J. In press.Google Scholar
  7. 7.
    Filizola M, Weinstein H. Structural models for dimerization of G-protein coupled receptors: the opioid receptor homodimers.Biopolymers. 2002;66:317–325.PubMedCrossRefGoogle Scholar
  8. 8.
    Filizola M, Guo W, Javitch JA, Weinstein H. Oligomerization domains in G-protein coupled receptors: insights into the structural basis of GPCR association. In: Devi LA, ed.The G-Protein Coupled Receptor Handbook Totowa, NJ: Humana Press Inc; 2005.Google Scholar
  9. 9.
    Beuming T, Skrabanek L, Niv MY, Mukherjee P, Weinstein H. PDZBase: a protein-protein interaction database for PDZ-domains.Bioinformatics. 2005;21:827–828.PubMedCrossRefGoogle Scholar
  10. 10.
    Chang CW, Hassan SA, Weisstein H. Determinants for specificity in binding to the PDZ domain of PICK1.Biophys J. 2004;86:96a.Google Scholar
  11. 11.
    Madsen KL, Beuming T, Niv MY, et al. Molecular determinants for the complex binding specificity of the PDZ domain in pick I.J Biol Chem. 2005;280:20539–20548.PubMedCrossRefGoogle Scholar
  12. 12.
    Slepchenko BM, Schaff JC, Macara I, Loew LM. Quantitative cell biology with the Virtual Cell.Trends Cell Biol. 2003;13:570–576.PubMedCrossRefGoogle Scholar
  13. 13.
    Slepchenko BM, Schaff JC, Carson JH, Loew LM. Computational cell biology: spatiotemporal simulation of cellular events.Annu Rev Biophys Biomol Struct. 2002;31:423–441.PubMedCrossRefGoogle Scholar
  14. 14.
    Wachman ES, Poage RE, Stiles JR, Farkas DL, Meriney SD. Spatial distribution of calcium entry evoked by single action protentials within the presynaptic active zone.J Neurosci. 2004;24:2877–2885.PubMedCrossRefGoogle Scholar
  15. 15.
    Campagne F, Neves S, Chang CW, et al. Quantitative information management for the biochemical computation of cellular networks.Sci STKE. 2004;2004:p111Google Scholar
  16. 16.
    Ebersole BJ, Visiers I, Weinstein H, Sealfon SC. Molecular basis of partial agonism: orientation of indoleamine ligands in the binding pocket of the human 5-HT2A serotonin receptor determines relative efficacy.Mol Pharmacol. 2003;63:36–43.PubMedCrossRefGoogle Scholar
  17. 17.
    Visiers I, Ebersole BJ, Dracheva B, Ballesteros JA, Sealfon SC, Weinstein H. Structural motifs as functional microdomains in G-protein-coupled receptors: energetic considerations in the mechanism of activation of the serotonin 5-HT2A receptor by disruption of the ionic lock of the arginine cage.Int J Quantum Chem. 2002;88:65–75.CrossRefGoogle Scholar
  18. 18.
    Prioleau C, Visiers I, Ebersole BJ, Weinstein H, Sealfon SC. Conserved helix 7 tyrosine acts as a multistate conformational switch in the 5HT2C receptor: identification of a novel “locked-on” phenotype and double revertant mutations.J Biol Chem. 2002;277:36577–36584.PubMedCrossRefGoogle Scholar
  19. 19.
    Gonzalez-Maeso J, Yuen T, Ebersole BJ, et al. Transcriptome fingerprints distinguish hallcuinogenic and nonhallucinogenic 5-hydroxytryptamine 2A receptor agonist effects in mouse somatosensory cortex.J Neurosci. 2003;23:8836–8843.PubMedGoogle Scholar
  20. 20.
    Gingrich JA, Ansorge MS, Merker R, Weisstaub N, Zhou M. New lessons from knockout mice: the role of serotonin during development and its possible contribution to the origins of neuropsychiatric disorders.CNS Spectr. 2003;8:572–577.PubMedGoogle Scholar
  21. 21.
    Ebersole BJ, Sealfon SC. Strategies for Mapping the Binding Site of the Serotonin 5HT2A Receptor. In: Iyengar R, Hildebrandt J, eds.Methods in Enzymology. San Diego, CA: Academic Press, 2001.Google Scholar
  22. 22.
    Beuming T, Weinstein H. A knowledge-based scale for the analysis and prediction of buried and exposed faces of transmembrane domain proteins.Bioinformatics. 2004;20:1822–1835.PubMedCrossRefGoogle Scholar
  23. 23.
    Ebersole BJ, Visiers I, Weinstein H, Sealfon SC. Molecular basis of partial agonism: orientation of indoleamine ligands in the binding pocket of the human serotonin 5-HT2A receptor determines relative efficacy.Mol Pharmacol. 2003;63:36–43.PubMedCrossRefGoogle Scholar
  24. 24.
    Ballesteros J, Kitanovic S, Guarnieri F, et al. Functional microdimains in G-protein-coupled receptors: the conserved argininecage motif in the gonadotropin-releasing hormone receptor.J Biol Chem. 1998;273:10445–10453.PubMedCrossRefGoogle Scholar
  25. 25.
    Javitch JA. The ants go marching 2 by 2: oligomeric structure of G-protein-coupled receptors.Mol Pharmacol. 2004;66:1077–1082.PubMedCrossRefGoogle Scholar
  26. 26.
    Filizola M, Olmea O, Weinstein H. Prediction of heterodimerization interfaces of G-protein coupled receptors with a new subtractive correlated mutation method.Protein Eng. 2002;15:881–885.PubMedCrossRefGoogle Scholar
  27. 27.
    Filipek S, Teller DC, Palczewski K, Stenkamp R. The crystallographic model of rhodopsin and its use in studies of other G protein-coupled receptors.Annu Rev Biophys Biomol Struct. 2003;32:375–397.PubMedCrossRefGoogle Scholar
  28. 28.
    Filipek S, Krzysko KA, Fotiadis D, et al. A concept for G protein activation by G protein-coupled receptor dimers: the transducin/rhodopsin interface.Photochem Photobiol Sci. 2004;3:628–638.PubMedCrossRefGoogle Scholar
  29. 29.
    Hoffimann C, Gaietta G, Bunemann M, et al. A FlAsH-based FRET approach to determine G protein-coupled receptor activation in living cells.Nat Methods. 2005;2:171–176.CrossRefGoogle Scholar
  30. 30.
    Zhuang X, Masson J, Gingrich JA, Rayport S, Hen R. Targeted gene expression in dopamine and serotonin neurons of the mouse brain.J Neurosci Methods. 2005;143:27–32.PubMedCrossRefGoogle Scholar
  31. 31.
    Ballesteros JA, Shi L, Javitch JA. Structural mimicry in G protein-coupled receptors: implications of the high-resolution structure of rhodopsin for structure-function analysis of rhodopsin-like receptors.Mol Pharmacol. 2001;60:1–19.PubMedGoogle Scholar
  32. 32.
    Huang P, Li J, Chen C, Visiers I, Weinstein H, Liu-Chen LY. Functional role of a conserved motif in TM6 of the rat mu opioid receptor: constitutively active and inactive receptors results from substitutions of Thr6.34(279) with Lys and Asp.Biochemistry. 2001;40:13501–13509.PubMedCrossRefGoogle Scholar
  33. 33.
    Flanagan CA, Zhou W, Chi L, et al. The functional microdomain in transmembrane helices 2 and 7 regulates expression, activation, and coupling pathways of the gonadotropin-releasing horm one receptor.J Biol Chem. 1999;274:28880–28886.PubMedCrossRefGoogle Scholar
  34. 34.
    Xu W, Ozdener F, Li JG, et al. Functional role of the spatial proximity of Asp 2 50(114) in TMH2 and Asn7.49(332) in TMH7 of the m opioid receptor.FEBS Lett. 1999;447:318–324.PubMedCrossRefGoogle Scholar
  35. 35.
    Decaillot FM, Befort K, Filliod D, Yue S, Walker P, Kieffer BL. Opiodd receptor random mutagenesis reveals a mechanism for G protein-coupled receptor activation.Nat Struct Biol. 2003;10:629–636.PubMedCrossRefGoogle Scholar
  36. 36.
    Janz JM, Farrens DL. Rhodopsin activation exposes a key hydrophobic binding site for the transducin alpha-subunit C terminus.J Biol Chem. 2004;279:29767–29773.PubMedCrossRefGoogle Scholar
  37. 37.
    Shapiro DA, Kristiansen K, Weiner DM, Kroeze WK, Roth BL. Evidence for a model of agonist-induced activation of 5-hydroxytryptamine 2A serotonin receptors that involves the disruption of a strong ionic interaction between helices 3 and 6.J Biol Chem. 2002;277:11441–11449.PubMedCrossRefGoogle Scholar
  38. 38.
    Kroeze WK, Kristiansen K, Roth BL. Molecular biology of serotonin receptors structure and function at the molecular level.Curr Top Med Chem. 2002;2:507–528.PubMedCrossRefGoogle Scholar
  39. 39.
    Meng EC, Bourne HR. Receptor activation: what does the rhodopsin structure tell us?.Trends Pharmacol Sci. 2001;22:587–593.PubMedCrossRefGoogle Scholar
  40. 40.
    Gerber BO, Meng EC, Dotsch V, Baranski TJ, Bourne HR. An activation switch in the ligand binding pocket of the C5a receptor.J Biol Chem. 2001;276:3394–3400.PubMedCrossRefGoogle Scholar
  41. 41.
    Ghanouni P, Steenhius JJ, Farrens DL, Kobilka BK. Agonist-induced conformational changes in the G-protein-coupling domain of the beta 2 adrenergic receptor.Proc Natl Acad Sci USA 2001;98:5997–6002.PubMedCrossRefGoogle Scholar
  42. 42.
    Ballesteros JA, Jensen AD, Liapakis G, et al. Activation of the beta 2-adrenergic receptor involves disruption of an ionic lock between the cytoplasmic ends of transmembrane segments 3 and 6.J Biol Chem. 2001;276:29171–29177.PubMedCrossRefGoogle Scholar
  43. 43.
    Gether U. Uncovering molecular mechanisms involved in activation of G protein-coupled receptors.Endocr Rev. 2000;21:90–113.PubMedCrossRefGoogle Scholar
  44. 44.
    Gether U, Asmar F, Meinild AK, Rasmussen SG. Structural basis for activation of G-protein-coupled receptors.Pharmacol Toxicol. 2002;91:304–312.PubMedCrossRefGoogle Scholar
  45. 45.
    Palczewski K, Kumasaka T, Hori T, et al. Crystal structure of rhodopsin: a G-protein coupled receptors.Science. 2000;289:739–745.PubMedCrossRefGoogle Scholar
  46. 46.
    Okada T, Ernst OP, Palczewski K, Hofmann KP. Activation of rhodopsin: new insights from structural and biochemical studies.Trends Biochem Sci. 2001;26:318–324.PubMedCrossRefGoogle Scholar
  47. 47.
    Stenkamp RE, Teller DC, Palczewski K. Crystal structure of rhodopsin: a G-protein-coupled receptors.ChemBioChem. 2002;3:963–967.PubMedCrossRefGoogle Scholar
  48. 48.
    Filipek S, Stenkamp RE, Teller DC, Palczewski K. G protein-coupled receptor rhodopsin: a prospectus.Annu Rev Physiol. 2003;65:851–879.PubMedCrossRefGoogle Scholar
  49. 49.
    Fritze O, Filipek S, Kuksa V, Palczewski K, Hofmann KP, Ernst OP. role of the conserved NPxxY(x)5,6F motif in the rhodopsin ground state and during activations.Proc natl Acad Sci USA. 2003;100:2290–2295.PubMedCrossRefGoogle Scholar
  50. 50.
    Kalatskaya I, Schussler S, Blauka A, et al. Mutation of tyrosine in te conserved NPXXY sequence leads to constitutive phosphorylation and internatlization, but not signaling, of the human B2 bradykinin receptor.J Biol Chem. 2004;279:31268–31276.PubMedCrossRefGoogle Scholar
  51. 51.
    Ballesteros JA, Weinstein H. Integrated methods for the construction of three-dimensional models and computational probing of structure-function relations in G protein-coupled receptors. In: Seafon SC, ed.Receptor Molecular Biology. San Diego, CA: Academic Press, 1995:366–428.CrossRefGoogle Scholar
  52. 52.
    Lin SW, Sakmar TP. Specific tryptophan UV-absorbance changes are probes of the transition of rhodopsin to its active state.Biochemistry. 1996;35:11149–11159.PubMedCrossRefGoogle Scholar
  53. 53.
    Shi L, Javitch JA. The second extracellular loop of the dopamine D2 receptor lines the binding-site crevice.Proc Natl Acad Sci USA. 2004;101:440–445.PubMedCrossRefGoogle Scholar
  54. 54.
    Singh R, Hurst DP, Barnett-Norris J, Lynch DL, Reggio PH, Guarnieri F. Activation of the cannabinoid CB1 receptor may involve a W6 48/F3 rotamer toggle switch.J Pept Res. 2002;60:357–370.PubMedCrossRefGoogle Scholar
  55. 55.
    Shi L, Liapakis G, Xu R, Guarnieri F, Ballesteros JA, Javitch JA, Beta 2 adrenergic receptor activation: modulation of the proline kink in transmembrane 6 by a rotamer toggle switch.J Biol Chem. 2002;277:40989–40996.PubMedCrossRefGoogle Scholar
  56. 56.
    McAllister SD, Hurst DP, Barnett-Norris J, Lynch D, Reggio PH, Abood ME. Structural mimicry in class A GPCR rotamer toggle switches: the importance of the F3. 36(201)/W6.48(357) interaction in cannabinoid CB1 receptor activation.J Biol Chem. 2004;279:48024–48037.PubMedCrossRefGoogle Scholar
  57. 57.
    McAllister SD, Rizvi G, Anavi-Goffer S, et al. An aromatic microdomain at the cannabinoid CB(1) receptor constitutes an agonist/ inverse agonist binding region.J Med Chem. 2003;46:5139–5152.PubMedCrossRefGoogle Scholar
  58. 58.
    Gay EA, Urban JD, Nichols DE, Oxford GS, Mailman RB. Functional selectivity of D2 receptor ligands in a Chinese hamster ovary hD2L cell line: evidence for induction of ligand-specific receptor states.Mol Pharmacol. 2004;66:97–105.PubMedCrossRefGoogle Scholar
  59. 59.
    Mottola DM, Kilts JD, Lewis MM, et al. Functional selectivity of dopamine receptor agonists. 1. Selective activation of postsynaptic dopamine D2 receptors linked to adenylate cyclase.J Pharmacol Exp Ther. 2002;301:1166–1178.PubMedCrossRefGoogle Scholar
  60. 60.
    Ghanouni P, Gryczynski Z, Steenhuis JJ, et al. Functionally different agonists induce distince conformations in the G protein coupling domain of the beta 2 adrenergic receptor.J Biol Chem. 2001;276;24433–24436.PubMedCrossRefGoogle Scholar
  61. 61.
    McLaughlin JN, Shen L, Holinstat M, Brooks JD, Dibenedetto E, Hamm HE. Functional selectivity of G protein signaling by agonist peptides and throm bin for the protease-activated receptor-1.J Biol Chem. 2005;280:25048–25059.PubMedCrossRefGoogle Scholar
  62. 62.
    Vilardaga JP, Steinmeyer R, Harms GS, Lohse MJ. Molecular basis of inverse agonism in a G protein-coupled receptor.Nature Chem Biol. 2005;1:25–28.CrossRefGoogle Scholar
  63. 63.
    Javitch JA, Ballesteros JA, Weinstein H, Chen J. A cluster of aromatic residues in the sixth membrane-spanning segment of the dopamine D2 receptor is accessible in the binding site crevice.Biochemistry. 1998;37:998–1006.PubMedCrossRefGoogle Scholar
  64. 64.
    Javitch JA, Ballesteros JA, Weinstein H, Chen J. A cluster of aromatic residues in the sixth membrane-spanning segment of the dopamine D2 receptor is accessible in the binding-site crevice.Biochemistry. 1998;37:998–1006.PubMedCrossRefGoogle Scholar
  65. 65.
    Filizola M, Hassan SA, Artoni A, Coller BS, Weinstein H. Mechanistic insights from a refined 3-dimensional model of integrin alphaIIbbeta3.J Biol Chem. 2004;279:24624–24630.PubMedCrossRefGoogle Scholar
  66. 66.
    Liggett SB. Update on current concepts of the molecular basis of beta2-adrenergic receptor signaling.J Allergy Clin Immunol. 2002;110:S223-S227.PubMedCrossRefGoogle Scholar
  67. 67.
    McAllister SD, Hurst DP, Barnett-Norris J, Lynch D, Reggio PH, Abood ME. Structural mimicry in class A G protein-coupled receptor rotamer toggle switches: the importance of the F3. 36(201)/W6.48(357) interaction in cannabinoid CB1 receptor activation.J Biol Chem. 2004;279:48024–48037.PubMedCrossRefGoogle Scholar
  68. 68.
    Mehler EL, Periole X, Hassan SA, Weinstein H. Key issues in the computational simulation of GPCR function: representation of loop domains.J Comput Aided Mol Des. 2002;16:841–853.PubMedCrossRefGoogle Scholar
  69. 69.
    Visiers I, Hassan SA, Weinstein H. Differences in conformational properties of the second intracellular loop (IL2) in 5HT(2C) receptors modified by RNA editing can account for G protein coupling efficiency.Protein Eng. 2001;14:409–414.PubMedCrossRefGoogle Scholar
  70. 70.
    McGrew L, Price RD, Hackler E, Chang MS, Sanders-Bush E. RNA editing of the human serotonin 5-HT2C receptor disrupts transactivation of the small G-protein RhoA.Mol Pharmacol. 2004;65:252–256.PubMedCrossRefGoogle Scholar
  71. 71.
    Niswender CM, Copeland SC, Herrick-Davis K, Emeson RB, Sanders-Bush E. RNA editing of the human serotonin 5-hydroxytryptamine 2C receptor silences constitutive activity.J Biol Chem. 1999;274:9472–9478.PubMedCrossRefGoogle Scholar
  72. 72.
    Hassan SA, Mehler EL, Zhang D, Weinstein H. Molecular dynamics simulations of peptides and proteins with a continuum electrostatic model based on screened Coulomb potentials.Proteins. 2003;51:109–125.PubMedCrossRefGoogle Scholar
  73. 73.
    Hassan SA, Mehler EL, Weinstein H. Structure calculations of protein segments connecting domains with defined secondary structure: a simulated annealing monte carlo combined with biased scaled collective variables technique. In: Hark K, Schlick T, eds.Lecture Notes in Computational Science and Engineering, New York, NY: Springer Verlag, Ag; 2002:197–231.Google Scholar
  74. 74.
    Sankararamakrishnan R, Weinstein H. Surface tension parameterization in molecular dynamics simulations of a phospholipidbilayer membrane: calibration and effects.J Phys Chem B. 2004;108:11802–11811.CrossRefGoogle Scholar
  75. 75.
    Fong SL, Tsin AT, Bridges CD, Liou GI. Detergents for extraction of visual pigments: types, solubilization, and stability.Methods Enzymol. 1982;81:133–140.PubMedGoogle Scholar
  76. 76.
    Liang Y, Fotiadis D, Filipek S, Saperstein DA, Palczewski K, Engel A. Organization of the G protein-coupled receptors rhodopsin and opsin in native membranes.J Biol Chem. 2003;278:21655–21662.PubMedCrossRefGoogle Scholar
  77. 77.
    Sankararamakrishnan R, Weinstein H. Molecular dynamics simulations predict a tilted orientation for the helical region of dynorphin A(1–17) in dimyristoylphosphatidylcholine bilayers.Biophys J. 2000;79:2331–2344.PubMedCrossRefGoogle Scholar
  78. 78.
    Sankararamakrishnan R, Weinstein H. Positioning and stabilization of dynorphin peptides in membrane bilayers: the mechanistic role of aromatic and basic residues revealed from comparative MD simulations.J Phys Chem B. 2002;106:209–218.CrossRefGoogle Scholar
  79. 79.
    Tieleman DP, Berendsen HJ, Sansom MS. An alamethicin channel in a lipid bilayer: molecular dynamics simulations.Biophys J. 1999;76:1757–1769.PubMedGoogle Scholar
  80. 80.
    Marrink SJ, Berger O, Tieleman P, Jahnig F. Adhesion forces of lipids in a phospholipid membrane studied by molecular dynamics simulations.Biophys J. 1998;74:931–943.PubMedGoogle Scholar
  81. 81.
    Petrache HI, Dodd SW, Brown MF. Area per lipid and acyl length distributions in fluid phosphatidylcholines determined by (2)H NMR spectroscopy.Biophys J. 2000;79:3172–3192.PubMedGoogle Scholar
  82. 82.
    Bock G, Goode JA, eds. In silico simulation of biological processes, Novartis Foundation Symposium 247. In:Novartis Foundation Symposium. Vol 247 Chichester, UK: John Wiley & Sons; 2002:262.Google Scholar
  83. 83.
    Fall C, Marland ES, Wagner JM, Tyson JJ.Computational Cell Biology. New York, NY: Springer Verlag; 2002.Google Scholar
  84. 84.
    Brown KS, Hill CC, Calero GA, et al. The statistical mechanics of complex signaling networks: nerve growth factor signaling.Phys Biol. 2004;1:184–195.PubMedCrossRefGoogle Scholar
  85. 85.
    Barrios-Rodiles M, Brown KR, Ozdamar B, et al. High-throughput mapping of a dynamic signaling network in mammalian cells.Science. 2005;307:1621–1625.PubMedCrossRefGoogle Scholar
  86. 86.
    Loew LM. The Virtual Cell project.Novartis Found Symp. 2002;247:151–160. Discussion 160–161, 198–206, 244–252.PubMedGoogle Scholar
  87. 87.
    Loew LM, Schaff JC. The Virtual Cell: a software environment for computational cell biology.Trends Biotechnol. 2001;19:401–406.PubMedCrossRefGoogle Scholar
  88. 88.
    Sauro HM, Kholodenko BN. Quantitative analysis of signaling networks.Prog Biophys Mol Biol. 2004;86:5–43.PubMedCrossRefGoogle Scholar
  89. 89.
    Kurrasch-Orbaugh DM, Parrish JC, Watts VJ, Nichols DE. A complex signaling cascade links the serotonin2A receptor to phospholipase A2 activation: the involvement of MAP kinases.J Neurochem. 2003;86:980–991.PubMedCrossRefGoogle Scholar
  90. 90.
    Kurrasch-Orbaugh DM, Watts VJ, Barker EL, Nichols DE. Serotonin 5-hydroxytryptamine 2A receptor-coupled phospholipase C and phospholipase A2 signaling pathways have different receptor reserves.J Pharmacol Exp Ther. 2003;304:229–237.PubMedCrossRefGoogle Scholar
  91. 91.
    Akin D, Manier DH, Sanders-Bush E, Shelton RC. Decreased serotonin 5-HT2A receptor-stimulated phosphoinositide signaling in fibroblasts from melancholic depressed patients.Neuropsychopharmacology. 2004;29:2081–2087.PubMedCrossRefGoogle Scholar
  92. 92.
    Conn PJ, Sanders-Bush E. Selective 5HT-2 antagonists inhibit serotonin stimulated phosphatidylinositol metabolism in cerebral cortex.Neuropharmacology. 1984;23:993–996.PubMedCrossRefGoogle Scholar
  93. 93.
    Roth BL, Nakaki T, Chuang DM, Costa E. Aortic recognition sites for serotonin (5HT) are coupled to phospholipase C and modulate phosphatidylinositol turnover.Neuropharmacology. 1984;23:1223–1225.PubMedCrossRefGoogle Scholar
  94. 94.
    Sanders-Bush E, Tsutsumi M, Burris KD. Serotonin receptors and phosphatidylinositol turnover.Ann N Y Acad Sci. 1990;600:224–235.PubMedCrossRefGoogle Scholar
  95. 95.
    Berg KA, Maayani S, Goldfarb J, Scaramellini C, Leff P, Clarke WP. Effector pathway-dependent relative efficacy at serotonin type 2A and 2C receptors: evidence for agonist-directed trafficking of receptor stimulus.Mol Pharmacol. 1998;54:94–104.PubMedGoogle Scholar
  96. 96.
    Bhalla US, Ram PT, Iyengar R. MAP kinase phosphatase as a locus of flexibility in a mitogen-activated protein kinase signaling network.Science. 2002;297:1018–1023.PubMedCrossRefGoogle Scholar
  97. 97.
    Weng G, Bhalla US, Iyengar R. Complexity in biological signaling systems.Science. 1999;284:92–96.PubMedCrossRefGoogle Scholar
  98. 98.
    Bruggeman FJ, Kholodenko BN. Modular interaction strengths in regulatory networks: an example.Mol Biol Rep. 2002;29:57–61.PubMedCrossRefGoogle Scholar
  99. 99.
    Markevich NI, Hoek JB, Kholodenko BN. Signaling switches and bistability arising from multisite phosphorylation in protein kinase cascade.J Cell Biol. 2004;164:353–359.PubMedCrossRefGoogle Scholar

Copyright information

© American Association of Pharmaceutical Scientists 2005

Authors and Affiliations

  1. 1.Institute for Computational BiomedicineWeill Medical College of Cornell UniversityNew York
  2. 2.Department of Physiology and BiophysicsWeill Medical College of Cornell UniversityNew York

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