Bulletin of Mathematical Biology

, Volume 76, Issue 6, pp 1352–1375 | Cite as

Modulation of the cAMP Response by G\(\alpha _i\) and G\(\beta \gamma \): A Computational Study of G Protein Signaling in Immune Cells

Original Article
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Abstract

Cyclic AMP is important for the resolution of inflammation, as it promotes anti-inflammatory signaling in several immune cell lines. In this paper, we present an immune cell specific model of the cAMP signaling cascade, paying close attention to the specific isoforms of adenylyl cyclase (AC) and phosphodiesterase that control cAMP production and degradation, respectively, in these cells. The model describes the role that G protein subunits, including G\(\alpha _s\), G\(\alpha _i\), and G\(\beta \gamma \), have in regulating cAMP production. Previously, G\(\alpha _i\) activation has been shown to increase the level of cAMP in certain immune cell types. This increase in cAMP is thought to be mediated by \(\beta \gamma \) subunits which are released upon G\(\alpha \) activation and can directly stimulate specific isoforms of AC. We conduct numerical experiments in order to explore the mechanisms through which G\(\alpha _i\) activation can increase cAMP production. An important conclusion of our analysis is that the relative abundance of different G protein subunits is an essential determinant of the cAMP profile in immune cells. In particular, our model predicts that limited availability of \(\beta \gamma \) subunits may both \((i)\) enable immune cells to link inflammatory G\(\alpha _i\) signaling to anti-inflammatory cAMP production thereby creating a balanced immune response to stimulation with low concentrations of PGE2, and \((ii)\) prohibit robust anti-inflammatory cAMP signaling in response to stimulation with high concentrations of PGE2.

Keywords

Mathematical modeling CAMP G proteins Immune cells 

Supplementary material

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References

  1. Agard M, Asakrahand S, Morici LA (2013) PGE2 suppression of innate immunity during mucosal bacterial infection. Front Cell Infect Microbiol 3Google Scholar
  2. Aronoff   DM, Canetti C, Serezani CH, Luo M, Peters-Golden M (2005) Cutting edge: macrophage inhibition by cyclic amp: differential roles of protein kinase a and exchange protein directly activated by camp-1. J Immunol 174:595–599Google Scholar
  3. Baillie GS, MacKenzie SJ, McPhee I, Houslay MD (2000) Sub-family selective actions in the ability of erk2 map kinase to phosphorylate and regulate the activity of pde4 cyclic amp-specific phosphodiesterases. Brit J Pharmacol 131:811–819CrossRefGoogle Scholar
  4. Bariagaber AK, Whalen MN (2003) Decreased adenylyl cyclase and camp-dependent protein kinase activites inhibit the cytotoxic function of human natural killer cells. Hum Immunol 64:866–873CrossRefGoogle Scholar
  5. Bloemen PG, van dan Tweel MC, Hendricks PA, Engels F, Kester MH, van de Loo PG, Blomjous FJ, Nijkamp FP (1997) Increased cAMP levels in stimulated neutrophils inhibit their adhesion to human bronchial epithelial cells. AJP-Lung Physiol 272:L580–L587Google Scholar
  6. Blüml K, Schnepp W, Schröder S, Beyermann M, Macias M, Oschkinat H, Lohse MJ (1997) A small region in phosducin inhibits g-protein betagamma-subunit function. EMBO J 16:4908–4915CrossRefGoogle Scholar
  7. Bopp T, Dehzad N, Klein M, Stassen M, Schild H, Buhl R, Schmitt E, Taube C (2009) Inhibition if camp degradation improves t cell-mediated suppression. J Immunol 182:4017–4024CrossRefGoogle Scholar
  8. Boxer LA, Yasaka T, Butterick CJ, Tzeng DY, Baehner RL (1983) Comparative studies of functional characteristics of mononuclear cell subsets and granulocytes. Am J Pediatr Hematol Oncol 5:181–188CrossRefGoogle Scholar
  9. Bridge LJ, King JR, Hill SJ, Owen MR (2010) Mathematical modelling of signalling in a two-ligand g-protein coupled receptor system: agonist-antagonist competition. Math Biosci 223:115–132MathSciNetCrossRefMATHGoogle Scholar
  10. Bünemann M, Frank M, Lohse MJ (2003) Gi protein activation in intact cells involves subunit rearrangement rather than dissociation. Proc Natl Acad Sci USA 100:16077–16082CrossRefGoogle Scholar
  11. Bystrom J, Evans I, Newson J, Stables M, Toor I, van Rooijen N, Crawford M, Colville-Nash P, Farrow S, Gilroy DW (2008) Resolution phase macrophages possess a unique inflammatory phenotype that is controlled by camp. Blood 112:4117–4127CrossRefGoogle Scholar
  12. Cabrera-Vera TM, Vanhauwe J, Thomas TO, Medkova M, Preininger A, Mazzoni MR, Hamm HE (2003) Insights into g protein structure, function, and regulation. Endocr Rev 24:765–781CrossRefGoogle Scholar
  13. Cabrera-Vera TM, Vanhauwe J, Thomas TO, Medkova M, Preininger A, Mazzoni MR, Hamm HE (2003) Insights into g protein structure, function, and regulation. Endocr Rev 24:765–781CrossRefGoogle Scholar
  14. Casey LM, Pistner AR, Belmonte SL, Migdalovich D, Stolpnik O, Nwakanma FE, Vorobiof G, Dunaevsky O, Matavel A, Lopes CMB, Smrcka AV, Blaxall BC (2010) Small molecule disruption of gbetagamma signaling inhibits the progression of heart failure. Circ. Res. 107:532–539CrossRefGoogle Scholar
  15. Catherine Jin SL, Lan L, Zoudilova M, Conti M (2005) Specific role of phosphodiesterase 4B in lipopolysaccharide-induced signaling in mouse macrophages. J Immunol 175:1523–1531Google Scholar
  16. Chisari M, Saini DK, Cho J-H, Kalyanaraman V (2009) G protein subunit dissociation and translocation regulate cellular response to receptor stimulation. PLoS ONE 4:e7797CrossRefGoogle Scholar
  17. Clack JW, Springmeyer ML, Clark CR, Witzmann FA (2006) Transducin subunit stoichiometry and cellular distribution in rod outer segments. Cell Biol Int 30:829–835CrossRefGoogle Scholar
  18. Csukas S, Hanke CJ, Rewolinski D, Campbell WB (1998) Prostaglandin e2-induced aldosterone release is mediated by an ep2 receptor. Hypertension 31:575–581CrossRefGoogle Scholar
  19. Dessauer CW, Gilman AG (1996) Purification and characterization of a soluble form of mammalian adenylyl cyclase. J Biol Chem 271:16967–16974CrossRefGoogle Scholar
  20. Diel S, Klass K, Wittig B, Kleuss C (2006) Gbetagamma activation site in adenylyl cyclase type ii. adenyly cyclase type iii is inhibited by gbetagamma. J Biol Chem 281:288–294CrossRefGoogle Scholar
  21. Dong H, Zitt C, Auriga C, Hatzelmann A, Epstein PM (2010) Inhibition of pde3, pde4 and pde7 potentiates glucocorticoid-induced apoptosis and overcomes glucocorticoid resistance in cem t leukemic cells. Biochem Pharmacol 79:321–329CrossRefGoogle Scholar
  22. Duan B, Davis R, Sadat EL, Collins J, Sternweis PC, Yuan D, Jiang LI (2010) Distinct roles of adenylyl cyclase vii in regulating the immune responses in mice. J Immunol 185:335–344CrossRefGoogle Scholar
  23. Fallahi-Sichani M, Linderman JJ (2009) Lipid raft-mediated regulation of g-protein coupled receptor signaling by ligands which influence receptor dimerization: a computational study. PloS One 4:e6604CrossRefGoogle Scholar
  24. Fitzpatrick FA, Aguirre R, Pike JE et al (1980) The stability of 13,14-dihydro-15 keto-pge2. Prostaglandins 19:917–931CrossRefGoogle Scholar
  25. Flaherty P, Radhakrishnan ML, Dinh T, Rebres RA, Roach TI, Jordan MI, Arkin AP (2008) A dual receptor crosstalk model of g-protein-coupled signal transduction. PloS Comput Biol 4:e1000185MathSciNetCrossRefGoogle Scholar
  26. Friedman HGE, Johnson MD (1995) Beta-adrenoreceptor-g alpha s coupling decreases with age in rat aorta. Mol Pharmacol 63:772–778Google Scholar
  27. Gary M, Bokoch KB (1988) Subcellular localization and quantitation of the major neutrophil pertussis toxin sensitive substrate, gn. J Cell Biol 106:1927–1936CrossRefGoogle Scholar
  28. Grant P, Colman R (1984) Purification and characterization of a human platelet cyclic nucleotide phosphodiesterase. Biochemistry-US 23:1801–1807CrossRefGoogle Scholar
  29. Graziano MP, Freissmuth M, Gilman AG (1989) Expression of gs alpha in escherichia coli. purification and properties of two forms of protein. J Biol Chem 264:409–418Google Scholar
  30. Gribble FM, Loussouarn G, Tucker SJ, Zhao C, Nichols CG, Ashcroft FM (2000) A novel method for measurement of submembrane atp concentration. J Biol Chem 275:30046–30049CrossRefGoogle Scholar
  31. Guo R-F, Ward PA (2005) Role of c5a in inflammatory responses. Annu Rev Immunol 23:821–852CrossRefGoogle Scholar
  32. Höller C, Freissmuth M, Nanoff C (1999) G proteins as drug targets. cmls. Cell Mol Life Sci 55:257–270CrossRefGoogle Scholar
  33. Hollinger S, Helper JR (2002) Cellular regulation of rgs proteins: modulators and integrators of g protein signaling. Pharmacol Rev 54:527–559CrossRefGoogle Scholar
  34. Huber-Lang M, Younkin EM, Vidya Sarma J, Riedemann Niels, McGuire SR, Lu KT, Kunkel R, Younger JG, Zetoune FS, Ward PA (2002) Gerenation of c5a by phagocytic cells. Am J Pathol 161:1849–1859CrossRefGoogle Scholar
  35. Huey R, Hugli TE (1985) Characterization of a c5a receptor on human polymorphonuclear leukocytes (pmn). J Immunol 1:321–366Google Scholar
  36. Huntjens DRH, Spalding DJM, Danhof M (2006) Correlation between in vitro and in vivo concentration-effect relationships of naproxen in rats and healthy volunteers. Brit J Pharmocol 148:396–404CrossRefGoogle Scholar
  37. Huston E, Lumb S, Russell A, Catterall C, Ross A, Steele M, Bolger G, Perry M, Owens R, Houslay M (1997) Molecular cloning and transient expression in cos7 cells of a novel human pde4b camp-specific phosphodiesterase, hspde4b3. Biochem. J 328:549–558CrossRefGoogle Scholar
  38. Iancu RV, Jones SW, Harvey RD (2007) Compartmentation of camp signaling in cardiac myocytes: a computational study. Biophys J 92:3317–3331CrossRefGoogle Scholar
  39. Ikegami R, Sugimoto Y, Segi E, Katsuyama Masato, Karahashi H, Amano F, Maruyama T, Yamane H, Tsuchiya S, Ichikawa A (2001) The expression of prostaglandin e receptors ep2 and ep4 and their different regulation by lipopolysaccharide in c3h/hen peritoneal macrophages. J Immunol 166:4689–4696CrossRefGoogle Scholar
  40. Kalinski P (2012) Regulation of immune responses by prostaglandin e2. J Immunol 188:21–28CrossRefGoogle Scholar
  41. Kamal FA, Smrcka AV, Blaxall BC (2011) Taking the heart failure battle inside the cell: small molecule targeting of g beta gamma subunits. J Mol Cell Cardiol 51:462–467CrossRefGoogle Scholar
  42. Kambayashi T, Wallin R, Ljunggren H-G (2001) Camp-elevating agents suppress dendritic cell function. J Leukocyte Biol 70:903–910Google Scholar
  43. Katanaev V, Chornomorets M (2007) Kinetic diversity in g-protein-coupled receptor signaling. Biochem J 401:485–495CrossRefGoogle Scholar
  44. Kehrl JH (1998) Heterotrimeric g protein signaling: roles in immune function and fine-tuning by rgs proteins. Immunity 8:1–10CrossRefGoogle Scholar
  45. Kimple AJ, Bosch DE, Giguère PM, Siderovski DP (2011) Regulators of g-protein signaling and their g substrates: promises and challenges in their use as drug discovery targets. Pharmacol Rev 63:728–749CrossRefGoogle Scholar
  46. Kinzer-Ursem Tamara L, Linderman Jennifer J (2007) Both ligand- and cell-specific parameters control ligand agonism in a kinetic model of G protein coupled receptor signaling. PloS Comput Biol 3:e6Google Scholar
  47. Klos A, Tenner AJ, Johswich K-O, Ager RR, Reis ES, Köhlc J (2009) The role of the anaphylatoxins in health and disease. Mol Immun 46:2753–2766CrossRefGoogle Scholar
  48. Krombach F, Munzing S, Allmeling A-M, Tilman Gerlach J, Behr J, Dbrger M (1997) Cell size of alveolar macrophages: an interspecies comparison. Environ Health Persp 105:1261–1263CrossRefGoogle Scholar
  49. Lan K-L, Zhong H, Nanamori M, Neugib R (2000) Rapid kinetics of regulator of g-protein signaling (rgs)-mediated galphai and galphao deactivation. galpha specificity of rgs4 and rgs7. J Biol Chem 275:33497–33503CrossRefGoogle Scholar
  50. Lattin J, Zidar DA, Schroder K, Kellie S, Hume DA, Sweet MJ (2007) G-protein-coupled receptor expression, function, and signaling in macrophages. J Leukocyte Biol 82:16–30CrossRefGoogle Scholar
  51. Levitzki A, Klein S (2002) G-protein subunit dissociation is not an integral part of g-protein action. ChemBioChem 3:815–818CrossRefGoogle Scholar
  52. Liang S, Krauss JL, Domon H, McInosh ML, Hosur KB, Qu H, Li F, Tzekou A, Lambris JD, Hajishengallis G (2011) The c5a receptor impairs il-12? dependent clearance of porphyromonas gingivalis and is required for induction of periodontal bone loss. J Immunol 186:869–877CrossRefGoogle Scholar
  53. Litvin TN, Kamenetsky M, Zarifyan A, Buck J, Levin LR (2003) Kinetic properties of soluble adenylyl cyclase synergism between calcium and bicarbonate. J Biol Chem 278:15922–15926Google Scholar
  54. Lohse MJ, Hoffmann C, Nikolaev VO, Vilardaga J-P, Bünemann M (2007) Kinetic analysis of g protein?coupled receptor signaling using fluorescence resonance energy transfer in living cells. Adv Protein Chem 74:167–188CrossRefGoogle Scholar
  55. Lohse MJ, Hein P, Nikolaev VO, Vilardaga J-P, Bünemann M (2008) Kinetics of g-protein-coupled receptor signals in intact cells. Brit J Pharmacol 153:S125–S132CrossRefGoogle Scholar
  56. Mahadeo DC, Janka-Junttila M, Smoot RL, Roselova P, Parent CA (2007) A chemoattractant-mediated gi-coupled pathway activates adenylyl cyclase in human neutrophils. Mol Biol Cell 18:512–522CrossRefGoogle Scholar
  57. Makhlouf M, Aston SH, Hildebrandt J, Mehta N, Gettys TW, Halushka PV, Cook JA (1996) Alterations in macrophage G proteins are associated with endotoxin tolerance. Biochim Biophys Acta 1312:163–168Google Scholar
  58. Marino S, Hogue IB, Ray CJ, Kirschner DE (2008) A methodology for performing global uncertainty and sensitivity analysis in systems biology. J Theor Biol 254:178–196MathSciNetCrossRefGoogle Scholar
  59. Matthiesen K, Nielsen J (2011) Cyclic amp control measured in two compartments in hek293 cells: phosphodiesterase km is more important than phosphodiesterase localization. PLoS ONE 6:e24392CrossRefGoogle Scholar
  60. Maurya MR, Subramaniam S (2007) A kinetic model for calcium dynamics in raw 264.7 cells: 1. mechanisms, parameters, and subpopulational variability. Biophys J 93:709–728CrossRefGoogle Scholar
  61. Olianas MC, Ingianni A, Onali P (1998) Role of g protein betagamma subunits in muscarinic receptor-induced stimulation and inhibition of adenylyl cyclase activity in rat olfactory bulb. J Neurochem 70:2620–2627CrossRefGoogle Scholar
  62. Onaran HO, Costa T, Rodbard D (1992) Beta gamma subunits of guanine nucleotide-binding proteins and regulation of spontaneous receptor activity: thermodynamic model for the interaction between receptors and guanine nucleotide-binding protein subunits. Mol Pharmacol 43:245–256Google Scholar
  63. Ostrand-Rosenberg S, Sinha P (2009) Myeloid-derived suppressor cells: linking inflammation and cancer. J Immunol 182:4499–4506CrossRefGoogle Scholar
  64. Ostrom RS, Post SR, Insel PA (2000) Stoichiometry and compartmentation in g protein-coupled receptor signaling: implications for therapeutic interventions involving gs. J Pharmacol Exp Ther 294:407–412Google Scholar
  65. Penn RB, Benovic JL (2008) Regulation of heterotrimeric g protein signaling in airway smooth muscle. Proc Am Thorac Soc 5:47–57CrossRefGoogle Scholar
  66. Peters-Golden M (2009) Putting on the brakes: cyclic amp as a multipronged controller of macrophage function. Sci Signal 2:e37CrossRefGoogle Scholar
  67. Post SR, Hilal-Dandan R, Urasawa K, Brunton LL, Insel PA (1995) Quantification of signalling components and amplification in the beta-adrenergic-receptor-adenylate cyclase pathway in isolated adult rat ventricular myocytes. Biochem J 311:75–80CrossRefGoogle Scholar
  68. Ramstad C, Sundvold V, Johansen HK, Lea T (2000) Camp-dependent protein kinase inhibits t cell activation by phosphorylating ser-43 of raf-1 in the mapk/erk pathway. Cell Signal 12:557–563CrossRefGoogle Scholar
  69. Rasmussen SGF, DeVree BT, Zou Y, Kruse AC, Chung KY, Kobilka TS, Thian FS, Chae PS, Pardon E, Calinski D, Mathiesen JM, Shah STA, Lyons JA, Caffrey M, Gellman SH, Steyaert J, Skiniotis G, Weis WI, Sunahara RK, Kobilka BK (2011) Crystal structure of the beta2 adrenergic receptor-gs protein complex. Nature 477:549–555CrossRefGoogle Scholar
  70. Rich TC, Fagan KA, Tse TE, Schaack J, Cooper DMF, Karpen JW (2001) A uniform extracellular stimulus triggers distinct camp signals in different compartments of a simple cell. Proc Natl Acad Sci USA 98:13049–13054CrossRefGoogle Scholar
  71. Ross EM, Wilkie TM (2000) Gtpase-activating proteins for heterotrimeric g proteins: regulators of g protein signaling (rgs) and rgs-like proteins. Annu Rev Biochem 69:795–827CrossRefGoogle Scholar
  72. Rossi AG, McCutcheon JC, Roy N, Chilvers ER, Haslett C, Dransfield I (1998) Regulation of macrophage phagocytosis of apoptotic cells by camp. J Immunol 160:352–3568Google Scholar
  73. Rowe J, Finlay-Jones JJ, Nicholas TE, Bowden J, Morton S, Hart PH (1997) Inability of histamine to regulate tnf-alpha production by human alveolar macrophages. Am J Respir Cell Mol Biol 17:218–226CrossRefGoogle Scholar
  74. Ryan D, Ren K, Wu H (2011) Single-cell assays. Biomicrofluidics 5:021501CrossRefGoogle Scholar
  75. Ryzhov S, Zaynagetdinov R, Goldstein AE, Novitskiy SV, Blackburn MR, Biaggioni I, Feoktistov I (2008) Effect of a2b adenosine receptor gene ablation on adenosine-dependent regulation of proinflammatory cytokines. J Pharmacol Exp Ther 324:694–700CrossRefGoogle Scholar
  76. Sarvazyan NA, Remmers AE (1998) Determinants of gi1alpha and beta gamma binding. measuring high affinity interactions in a lipid environment using flow cytometry. J Biol Chem 273:7934–7940CrossRefGoogle Scholar
  77. Sarvazyan NA, Lim WK, Neubig RR (2002) Fluorescence analysis of receptor g protein interactions in cell membranes. Biochemistry-US 41:12858–12867CrossRefGoogle Scholar
  78. Satoh H, Delbridge LM, Blatter LA, Bers DM (1996) Surface:volume relationship in cardiac myocytes studied with confocal microscopy and membrane capacitance measurements: species-dependence and developmental effects. Biophys J 70:1494–1504CrossRefGoogle Scholar
  79. Saucerman JJ, Brunton LL, Michailova AP, McCulloch AD (2003) Modelling beta-adrenergic control of cardiac myocyte contractility in silico. J Biol Chem 278:47997–48003CrossRefGoogle Scholar
  80. Schudt C, Tenor H, Hatzelmann A (1995) Pde isoenzymes as targets for anti-asthma drugs. Eur Respir J 8:1179–1183CrossRefGoogle Scholar
  81. Shankaran H, Wiley HS, Resat H (2007) Receptor downregulation and desensitization enhance the information processing ability of signalling receptors. BCM Syst Biol 1:48CrossRefGoogle Scholar
  82. Shepard MC, Baillie GS, Stirling DI, Houslay MD (2004) Remodeling of the pde4 camp phosphodiesterase isoform profile upon monocyte-macrophage differentiation of human u937 cells. Brit J Pharmacol 142:339–351CrossRefGoogle Scholar
  83. Smrcka AV (2008) G protein beta gmma subuits: central mediators of g protein-coupled receptor signaling. Cell Mol Life Sci 65:2191–2214CrossRefGoogle Scholar
  84. Sreeramkumar V, Fresno M, Cuesta N (2012) Prostaglandin E2 and t cells: friends or foes? Immunol Cell Biol 90:579–586Google Scholar
  85. Sreermkumar V, Fresno M, Cuesta N (2011) Prostaglandin E2 and t cells: friends or foes? Immunol Cell Biol 90:1–8Google Scholar
  86. Sugimoto Y, Nakato T, Kita A, Hatae N, Tabata Hiroyuki, Tanaka S, Ichikawa A (2003) Functional domains essential for gs activity in prostaglandin ep2 and ep3 receptors. Life Sci 74:135–141CrossRefGoogle Scholar
  87. Tang W-J, Krupinski J, Gilman AG (1991) Expression and characterization of calmodulin-acitivated (type i) adenylylcyclase. J Biol Chem 266:8595–8603Google Scholar
  88. Taussig R, Quarmby LM, Gilman AG (1993) Regulation of purified type i and type ii adenylylcyclases by g protein betagamma subunits. J Biol Chem 268:9–12Google Scholar
  89. Ting-Beall HP, Needham D, Hochmuth RM (1993) Volume and osmotic properties of human neutrophils. Blood 81:277–2780Google Scholar
  90. Turcotte M, Tang W, Ross EM (2008) Coordinate regulation of g protein signaling via dynamic interactions of receptor and gap. PLoS Comput Biol 4:e1000148CrossRefGoogle Scholar
  91. Uezono Y, Kaibara M, Murasaki O, Taniyama K (2004) Involvement of g protein betagamma subunits in diverse signaling induced by gi/o-coupled receptors: study using the xenopus oocyte expression system. Am J Cell Physiol 287:C885–C894CrossRefGoogle Scholar
  92. Van Epsa N, Preininger AM, Alexander N (2011) Interaction of a G protein with an activated receptor opens the interdomain interface in the alpha subunit. Proc Natl Acad Sci USA 108:9420–9424Google Scholar
  93. Wang P, Myers J, Wu P, Cheewatrakoolpong B, Egan R, Motasim Billah M (1997) Expression, purification, and characterization of human camp-specific phosphodiesterase (pde4) subtypes a, b, c, and d. Biochem Biophys Res Commun 234:320–324CrossRefGoogle Scholar
  94. Wang M, Krauss JL, Domon H, Hosur KB, Liang S, Magotti P, Triantafilou M, Triantafilou K, Lambris JD, Hajishengallis G (2010) Microbial hijacking of complement toll-like receptor crosstalk. Sci Signal 3Google Scholar
  95. Wang P, Wu P, Ohleth KM, Egan RW, Billah MM (1999) Phosphodiesterase 4B2 is the predominant phosphodiesterase species and undergoes differential regulation of gene expression in human monocytes and neutrophils. Mol Pharmacol 56:170–174Google Scholar
  96. Watkins DC, Northup JK, Malbon CC (1987) Regulation of g-proteins in differentiation altered ratio of alpha to beta subunits in 3t3-l1 cells. J Biol Chem 262:10651–10657Google Scholar
  97. Wettschureck N, Offermanns S (2005) Mammalian g proteins and their cell type specific functions. Physiol Rev 85:1159–1204CrossRefGoogle Scholar
  98. Xin W, Tran TM, Richter W, Clark RB, Rich TC (2008) Roles of grk and pde4 activities in the regulation of beta adrenergic signaling. J Gen Physiol 131:349–364CrossRefGoogle Scholar
  99. Zahn S, Zwirner J, Spengler H-P, Götze O (1997) Chemoattractant receptors for interlukin-8 and c5a: expression on peripheral blood leukocytes and differential regulation on HL-60 and AML-193 cells by vitamin d3 and all-trans retinoic acid. Eur J Immunol 27:935–940Google Scholar

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© Society for Mathematical Biology 2014

Authors and Affiliations

  1. 1.Department of MathematicsMiddle Tennessee State UniversityMurfreesboroUSA
  2. 2.Department of MathematicsThe Ohio State UniversityColumbusUSA

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