Molecular Neurobiology

, Volume 56, Issue 4, pp 2685–2702 | Cite as

Docosahexaenoic Acid (DHA) Induced Morphological Differentiation of Astrocytes Is Associated with Transcriptional Upregulation and Endocytosis of β2-AR

  • Moitreyi Das
  • Sumantra DasEmail author


Docosahexaenoic acid (DHA), an important ω-3 fatty acid, is abundantly present in the central nervous system and is important in every step of brain development. Much of this knowledge has been based on studies of the role of DHA in the function of the neurons, and reports on its effect on the glial cells are few and far between. We have previously reported that DHA facilitates astrocyte differentiation in primary culture. We have further explored the signaling mechanism associated with this event. It was observed that a sustained activation of the extracellular signal-regulated kinase (ERK) appeared to be critical for DHA-induced differentiation of the cultured astrocytes. Prior exposure to different endocytic inhibitors blocked both ERK activation and differentiation of the astrocytes during DHA treatment suggesting that the observed induction of ERK-2 was purely endosomal. Unlike the β1-adrenergic receptor (β1-AR) antagonist, atenolol, pre-treatment of the cells with the β2-adrenergic receptor (β2-AR) antagonist, ICI-118,551 inhibited the DHA-induced differentiation process, indicating a downstream involvement of β2-AR in the differentiation process. qRT-PCR and western blot analysis demonstrated a significant induction in the mRNA and protein expression of β2-AR at 18–24 h of DHA treatment, suggesting that the induction of β2-AR may be due to transcriptional upregulation. Moreover, DHA caused activation of PKA at 6 h, followed by activation of downstream cAMP response element-binding protein, a known transcription factor for β2-AR. Altogether, the observations suggest that DHA upregulates β2-AR in astrocytes, which undergo endocytosis and signals for sustained endosomal ERK activation to drive the differentiation process.


Astrocytes β2-Adrenergic receptor Docosahexaenoic acid Endocytosis PKA GPR120 


Funding Information

The work was carried out from the financial assistance of the Council of Scientific & Industrial Research, New Delhi. MD was a recipient of fellowship also from the Council of Scientific & Industrial Research, New Delhi.

Compliance with Ethical Standards

Animal experimentation was approved by the institutional animal ethics committee appointed by CPCSEA (Committee for the Purpose of Control and Supervision of Experiments on Animals) of the animal welfare division under the Ministry of Environment and Forest, Government of India (Registration no. 147/CPCSEA).

Conflict of Interest

The authors declare that they have no conflict of interest.


  1. 1.
    Horrocks LA, Farooqui AA (2004) Docosahexaenoic acid in the diet: its importance in maintenance and restoration of neural membrane function. Prostaglandins Leukotrienes Essent. Fatty Acids 70:361–372Google Scholar
  2. 2.
    Innis SM (2007) Dietary (n-3) fatty acids and brain development. J Nutr 137:855–859PubMedGoogle Scholar
  3. 3.
    Tassoni D, Kaur G, Weisinger RS, Sinclair AJ (2008) The role of eicosanoids in the brain. Asia Pac J Clin Nutr 17:220–228PubMedGoogle Scholar
  4. 4.
    Luchtman DW, Song C (2013) Cognitive enhancement by omega-3 fatty acids from child-hood to old age: findings from animal and clinical studies. Neuropharmacology 64:550–565PubMedGoogle Scholar
  5. 5.
    Parletta N, Milte CM, Meyer BJ (2013) Nutritional modulation of cognitive function and mental health. J Nutr Biochem 24:725–743PubMedGoogle Scholar
  6. 6.
    de Urquiza AM, Liu S, Sjoberg M, Zetterstrom RH, Griffiths W, Sjovall J, Perlmann T (2000) Docosahexaenoic acid, a ligand for the retinoid X receptor in mouse brain. Science 290:2140–2144PubMedGoogle Scholar
  7. 7.
    Miyauchi S, Hirasawa A, Iga T, Liu N, Itsubo C, Sadakane K, Hara T, Tsujimoto G (2009) Distribution and regulation of protein expression of the free fatty acid receptor GPR120. Naunyn Schmiedeberg’s Arch Pharmacol 379:427–434Google Scholar
  8. 8.
    Oh DY, Talukdar S, Bae EJ, Imamura T, Morinaga H, Fan W, Li P, Lu WJ et al (2010) GPR120 is anomega-3 fatty acid receptor mediating potent anti-inflammatory and insulin-sensitizing effects. Cell 142:687–698PubMedPubMedCentralGoogle Scholar
  9. 9.
    Ma D, Zhang M, Larsen CP, Xu F, Hua W, Yamashima T, Mao Y, Zhou L (2010) DHA promotes the neuronal differentiation of rat neural stem cells transfected with GPR40. Gene 1330:1–8Google Scholar
  10. 10.
    Yamashima T (2015) ‘PUFA-GPR40-CREB signaling’ hypothesis for the adult primate neurogenesis. Prog Lipid Res 51:221–231Google Scholar
  11. 11.
    Wellhauser L, Belsham DD (2014) Activation of the omega-3 fatty acid receptor GPR120 mediates anti-inflammatory actions in immortalized hypothalamic neurons. J Neuroinflammation 11:60–73PubMedPubMedCentralGoogle Scholar
  12. 12.
    Gharami K, Das M, Das S (2015) Essential role of docosahexaenoic acid towards development of a smarter brain. Neurochem Int 89:51–62PubMedGoogle Scholar
  13. 13.
    Moore SA, Yoder E, Murphy S, Dutton GR, Spector AA (1991) Astrocytes, not neurons, produce docosahexaenoic acid (22:6-3) and arachidonic acid (20:4-6). J Neurochem 56:518–524PubMedGoogle Scholar
  14. 14.
    Moore SA (1994) Local synthesis and targeting of essential fatty acids at the cellular interface between blood and brain: a role for cerebral endothelium and astrocytes in the accretion of CNS docosahexaenoic acid. World Rev Nutr Diet 75:128–133PubMedGoogle Scholar
  15. 15.
    Bernoud N, Fenart L, Benistant C et al (1998) Astrocytes are mainly responsible for the polyunsaturated fatty acid enrichment in blood-brain barrier endothelial cells in vitro. J Lipid Res 39:1816–1824PubMedGoogle Scholar
  16. 16.
    Moore SA, Yoder E, Spector AA (1990) Role of the blood-brain barrier in the formation of long-chain omega-3 and omega-6 fatty acids from essential fatty acid precursors. J Neurochem 55:391–402PubMedGoogle Scholar
  17. 17.
    Moore SA (2001) Polyunsaturated fatty acid synthesis and release by brain-derived cells in vitro. J Mol Neurosci 16:195–200PubMedGoogle Scholar
  18. 18.
    Garcia MC, Kim HY (1997) Mobilization of arachidonate and docosahexaenoate by stimulation of the 5-HT2A receptor in rat C6 glioma cells. Brain Res 768:43–48PubMedGoogle Scholar
  19. 19.
    Kim HY, Edsall L, Garcia M, Zhang H (1999) The release of polyunsaturated fatty acids and their lipoxygenation in the brain. Adv Exp Med Biol 447:75–85PubMedGoogle Scholar
  20. 20.
    Strokin M, Sergeeva M, Reiser G (2003) Docosahexaenoic acid and arachidonic acid release in rat brain astrocytes is mediated by two separate isoforms of phospholipase A2 and is differently regulated by cyclic AMP and Ca2+. Br J Pharmacol 139:1014–1022PubMedPubMedCentralGoogle Scholar
  21. 21.
    Calderon F, Kim HY (2004) Docosahexaenoic acid promotes neurite growth in hippocampal neurons. J Neurochem 90:979–988PubMedGoogle Scholar
  22. 22.
    Cao D, Xue R, Xu J, Liu Z (2005) Effects of docosahexaenoic acid on the survival and neurite outgrowth of rat cortical neurons in primary cultures. J Nutr Biochem 16:538–546PubMedGoogle Scholar
  23. 23.
    Cao D, Kevala K, Kim J, Moon HS, Jun SB, Lovinger D, Kim HY (2009) Docosahexaenoic acid promotes hippocampal neuronal development and synaptic function. J Neurochem 111:510–521PubMedPubMedCentralGoogle Scholar
  24. 24.
    Champeil-Potokar G, Chaumontet C, Guesnet P, Lavialle M, Denis I (2006) Docosahexaenoic acid (22:6n-3) enrichment of membrane phospholipids increases gap junction coupling capacity in cultured astrocytes. Eur J Neurosci 24:3084–3090PubMedGoogle Scholar
  25. 25.
    Grintal B, Champeil-Potokar G, Lavialle M, Vancassel S, Breton S, Denis I (2009) Inhibition of astroglial glutamate transport by polyunsaturated fatty acids: evidence for a signaling role of docosahexaenoic acid. Neurochem Int 54:535–543PubMedGoogle Scholar
  26. 26.
    Ximenes da Silva A, Lavialle F, Gendrot G, Guesnet P, Alessandri JM, Lavialle M (2002) Glucose transport and utilization are altered in the brain of rats deficient in n-3 polyunsaturated fatty acids. J Neurochem 81:1328–1337PubMedGoogle Scholar
  27. 27.
    Pifferi F, Roux F, Langelier B et al (2005) (n-3) polyunsaturated fatty acid deficiency reduces the expression of both isoforms of the brain glucose transporter GLUT1 in rats. J Nutr 135:2241–2246PubMedGoogle Scholar
  28. 28.
    Champeil-Potokar G, Hennebelle M, Latour A, Vancassel S, Denis I (2016) Docosahexaenoic acid (DHA) prevents corticosterone-induced changes in astrocytes morphology and function. J Neurochem 136:1155–1167PubMedGoogle Scholar
  29. 29.
    Joardar A, Sen AK, Das S (2006) Docosahexaenoic acid facilitates cell maturation and beta-adrenergic transmission in astrocytes. J Lipid Res 47:571–581PubMedGoogle Scholar
  30. 30.
    Federoff S (1986) Prenatal ontogenesis of astrocytes. In: Federoff S, Vernadakis A (eds) Astrocytes: development, morphology, and regional specialization of astrocytes. Academic Press, Orlando, pp. 35–74Google Scholar
  31. 31.
    Lim R, Mitsunobu K, Li WKP (1973) Maturation-stimulating effect of brain extract and dibutyryl cyclic AMP on dissociated embryonic brain cells in culture. Exp Cell Res 79:243–246PubMedGoogle Scholar
  32. 32.
    Moonen G, Cam Y, Sensenbrenner M, Mandel P (1975) Variability of the effects of serum-free medium, dibutyryl cyclic AMP or theophylline on the morphology of cultured newborn astrocytcs. Cell Tissue Rex 163:365–372Google Scholar
  33. 33.
    Gavaret JM, Delbauffe DT, Chalaye DB, Pomerance M, Pierce M (1991) Thyroid hormone action: induction of morphological changes and protein secretion in astroglial cultures. Dev Brain Res 58:43–49Google Scholar
  34. 34.
    Paul S, Das S, Poddar R, Sarkar PK (1996) Effect of thyroid hormone in the morphological differentiation and maturation of astrocytes: temporal correlation with synthesis and organisation of actin. Eur J Neurosci 8:2361–2370PubMedGoogle Scholar
  35. 35.
    Rakic P (1972) Mode of cell migration to the superficial layers of fetal monkey neocortex. J Comp Neurol 145:61–81PubMedGoogle Scholar
  36. 36.
    Silver J, Lorenz SE, Wahlsten D, Coughlin J (1982) Axonal guidance during development of the great cerebral commissures: descriptive experimental studies, in vivo, on the role of preformed glial pathways. J Comp Neurol 210:10–29PubMedGoogle Scholar
  37. 37.
    Guillery RW, Walsh C (1987) Changing glial organization relates to changing fiber order in the developing optic nerve of ferrets. J Comp Neurol 265:203–217PubMedGoogle Scholar
  38. 38.
    Abe K, Saito H (2000) The p44/42 mitogen-activated protein kinase cascade is involved in the induction and maintenance of astrocyte stellation mediated by protein kinase C. Neurosci Res 36:251–257PubMedGoogle Scholar
  39. 39.
    Ueki T, Fujita M, Sato K, Asai K, Yamada K, Kato T (2001) Epidermal growth factor down-regulates connexin-43 expression in cultured rat cortical astrocytes. Neurosci Lett 313:53–56PubMedGoogle Scholar
  40. 40.
    Gharami K, Das S (2000) Thyroid hormone-induced morphological differentiation and maturation of astrocytes are mediated through the beta-adrenergic receptor. J Neurochem 75:1962–1969PubMedGoogle Scholar
  41. 41.
    Gharami K, Das S (2004) Delayed but sustained induction of mitogen-activated protein kinase activity is associated with β-adrenergic receptor-mediated morphological differentiation of astrocytes. J Neurochem 88:12–22PubMedGoogle Scholar
  42. 42.
    Grynberg A, Fournier A, Sergiel JP, Athias P (1995) Effect of docosahexaenoic acid and eicosapentaenoic acid in the phospholipids of rat heart muscle cells on adrenoceptor responsiveness and mechanism. J Mol Cell Cardiol 27:2507–2520PubMedGoogle Scholar
  43. 43.
    Ponsard B, Durot I, Delerive P, Oudot F, Cordelet C, Grynberg A, Athias P (1999) Cross-influence of membrane polyunsaturated fatty acids and hypoxia-reoxygenation on alpha- and beta-adrenergic function of rat cardiomyocytes. Lipids 34:457–466PubMedGoogle Scholar
  44. 44.
    Delerive P, Oudot F, Ponsard B, Talpin S, Sergiel JP, Cordelet C, Athias P, Grynberg A (1999) Hypoxia-reoxygenation and polyunsaturated fatty acids modulate adrenergic functions in cultured cardiomyocytes. J Mol Cell Cardiol 31:377–386PubMedGoogle Scholar
  45. 45.
    Skúladóttir GV, Schiöth HB, Gudbjarnason S (1993) Polyunsaturated fatty acids in heart muscle and alpha 1-adrenoceptor binding properties. Biochim Biophys Acta 1178:49–54PubMedGoogle Scholar
  46. 46.
    Begg DP, Puskás LG, Kitajka K, Ménesi D, Allen AM, Li D, Mathai ML, Shi JR et al (2012) Hypothalamic gene expression in ω-3 PUFA-deficient male rats before, and following, development of hypertension. Hypertens Res 35:381–387PubMedGoogle Scholar
  47. 47.
    Ghosh M, Gharami K, Paul S, Das S (2005) Thyroid hormone-induced morphological differentiation and maturation of astrocytes involves activation of protein kinase A and ERK signaling pathway. Eur J Neurosci 22:1609–1617PubMedGoogle Scholar
  48. 48.
    Rashid MA, Katakura M, Kharebava G, Kevala K, Kim HY (2013) N-docosahexaenoylethanolamine is a potent neurogenic factor for neural stem cell differentiation. J Neurochem 125:869–884PubMedPubMedCentralGoogle Scholar
  49. 49.
    Park T, Chen H, Kevala K, Lee JW, Kim HY (2016) N-docosahexaenoylethanolamine ameliorates LPS-induced neuroinflammation via cAMP/PKA-dependent signaling. J Neuroinflammation 13:284PubMedPubMedCentralGoogle Scholar
  50. 50.
    Angulo-Rojo C, Manning-Cela R, Aguirre A, Ortega A, López-Bayghen E (2013) Involvement of the Notch pathway in terminal astrocytic differentiation: role of PKA. ASN Neuro 5:e00130PubMedPubMedCentralGoogle Scholar
  51. 51.
    Takahashi M, Li Y, Dillon TJ, Stork PJS (2017) Phosphorylation of Rap1 by cAMP-dependent protein kinase (PKA) creates a binding site for KSR to sustain ERK activation by cAMP. J Biol Chem 292:1449–1461PubMedGoogle Scholar
  52. 52.
    Dugan LL, Kim JS, Zhang Y, Bart RD, Sun Y, Holtzman DM, Gutmann DH (1999) Differential effects of cAMP in neurons and astrocytes. Role of B-raf. J Biol Chem 274:25842–25848PubMedGoogle Scholar
  53. 53.
    Wu J, Dent P, Jelinek T, Wolfman A, Weber MJ, Sturgill TW (1993) Inhibition of the EGF-activated MAP kinase signaling pathway by adenosine 3’,5’-monophosphate. Science 262:1065–1106PubMedGoogle Scholar
  54. 54.
    Cook SJ, McCormick F (1993) Inhibition by cAMP of Ras-dependent activation of Raf. Science 262:1069–1072PubMedGoogle Scholar
  55. 55.
    Marshall CJ (1995) Specificity of receptor tyrosine kinase signaling: transient versus sustained extracellular signal-regulated kinase activation. Cell 80:179–185PubMedGoogle Scholar
  56. 56.
    Kao S, Jaiswal RK, Kolch W, Landreth GE (2001) Identification of the mechanisms regulating the differential activation of the mapk cascade by epidermal growth factor and nerve growth factor in PC12 cells. J Biol Chem 276:18169–18177PubMedGoogle Scholar
  57. 57.
    Sun P, Watanabe H, Takano K, Yokoyama T, Fujisawa J, Endo T (2006) Sustained activation of M-Ras induced by nerve growth factor is essential for neuronal differentiation of PC12 cells. Genes Cells 11:1097–1113PubMedGoogle Scholar
  58. 58.
    Tang G, Dong X, Huang X, Huang XJ, Liu H, Wang Y, Ye WC, Shi L (2015) A natural diarylheptanoid promotes neuronal differentiation via activating ERK and PI3K-Akt dependent pathways. Neuroscience 303:389–401PubMedGoogle Scholar
  59. 59.
    Zogovic N, Tovilovic-Kovacevic G, Misirkic-Marjanovic M, Vucicevic L, Janjetovic K, Harhaji-Trajkovic L, Trajkovic V (2015) Coordinated activation of AMP-activated protein kinase, extracellular signal-regulated kinase, and autophagy regulates phorbol myristate acetate-induced differentiation of SH-SY5Y neuroblastoma cells. J Neurochem 133:223–232PubMedGoogle Scholar
  60. 60.
    Das M, Ghosh M, Das S (2016) Thyroid hormone-induced differentiation of astrocytes is associated with transcriptional upregulation of β-arrestin-1 and β-adrenergic receptor-mediated endosomal signaling. Mol Neurobiol 53:5178–5190PubMedGoogle Scholar
  61. 61.
    DeFea KA, Zalevsky J, Thoma MS, Déry O, Mullins RD, Bunnett NW (2000) β-Arrestin–dependent endocytosis of proteinase-activated receptor 2 is required for intracellular targeting of activated ERK1/2. J. Cell Biol 148:1267–1281PubMedPubMedCentralGoogle Scholar
  62. 62.
    Murphy JE, Padilla BE, Hasdemir B, Cottrell GS, Bunnett NW (2009) Endosomes: a legitimate platform for the signaling train. Proc Natl Acad Sci U S A 106:17615–17622PubMedPubMedCentralGoogle Scholar
  63. 63.
    Luttrell LM, Gesty-Palmer D (2010) Beyond desensitization: physiological relevance of arrestin-dependent signaling. Pharmacol Rev 62:305–330PubMedPubMedCentralGoogle Scholar
  64. 64.
    Ghosh M, Das S (2007) Increased β2-adrenergic receptor activity by thyroid hormone possibly leads to differentiation and maturation of astrocytes in culture. Cell Mol Neurobiol 27:1007–1021PubMedGoogle Scholar
  65. 65.
    Deb I, Das S (2011) Thyroid hormones protect astrocytes from morphine-induced apoptosis by regulating nitric oxide and pERK 1/2 pathways. Neurochem Int 58:861–871PubMedGoogle Scholar
  66. 66.
    Samuels NH, Stanley F, Casanova Z (1979) Depletion of L-3,5,3′- triiodothyronine and L-thyroxine in euthyroid calf serum for use in cell culture studies of the action of thyroid hormone. Endocrinol 105:80–85Google Scholar
  67. 67.
    Das M, Das S (2016) Identification of cytotoxic mediators and their putative role in the signaling pathways during docosahexaenoic acid (DHA)-induced apoptosis of cancer cells. Apoptosis 21:1408–1421PubMedGoogle Scholar
  68. 68.
    Lowry OH, Rosebrough NJ, Farr AL, Randall RJ (1951) Protein measurement with the Folin-phenol reagent. J Biol Chem 193:265–275PubMedGoogle Scholar
  69. 69.
    Impey S, Obrietan K, Wong ST, Poser S, Yano S, Wayman G, Deloulme JC, Chan G et al (1998) Cross talk between ERK and PKA is required for Ca2+ stimulation of CREB-dependent transcription and ERK nuclear translocation. Neuron 21:869–883PubMedGoogle Scholar
  70. 70.
    Wu C, Lai CF, Mobley WC (2001) Nerve growth factor activates persistent Rap1 signaling in endosomes. J Neurosci 21:5406–5416PubMedGoogle Scholar
  71. 71.
    Er EE, Mendoza MC, Mackey AM, Rameh LE, Blenis J (2013) AKT facilitates EGFR trafficking and degradation by phosphorylating and activating PIKfyve. Sci Signal 6:ra45PubMedGoogle Scholar
  72. 72.
    Zastrow MV (2002) Regulation of G protein coupled receptors by phosphorylation and endocytosis in Neuropsychopharmacology: the fifth generation of progress. Edited by Davis K. L., Charney D., Coyle J. T. And Nemeroff C. 59-70. ACNP publications.Google Scholar
  73. 73.
    Drake MT, Shenoy SK, Lefkowitz RJ (2006) Trafficking of G protein-coupled receptors. Circ Res 99:570–582PubMedGoogle Scholar
  74. 74.
    Hanyaloglu AC, von Zastrow M (2008) Regulation of GPCRs by endocytic membrane trafficking and its potential implications. Annu Rev Pharmacol Toxicol 48:537–568Google Scholar
  75. 75.
    Ferguson SSG, Barak LS, Zhang J, Caron MG (1996) G-protein-coupled receptor regulation: role of G-protein-coupled receptor kinases and arrestins. Can J Physiol Pharmacol 74:1095–1110PubMedGoogle Scholar
  76. 76.
    Collins S, Altschmied J, Herbsman O, Caron MG, Mellon PL, Lefkowitz RJ (1990) A cAMP response element in the beta 2-adrenergic receptor gene confers transcriptional autoregulation by cAMP. J Biol Chem 265:19330–19335PubMedGoogle Scholar
  77. 77.
    Wassall SR, Stillwell W (2009) Polyunsaturated fatty acid-cholesterol interactions: domain formation in membranes. Biochim Biophys Acta 1788:24–32PubMedGoogle Scholar
  78. 78.
    Shaikh SR, Teague H (2012) N-3 fatty acids and membrane microdomains: from model membranes to lymphocyte function. Prostaglandins Leukot Essent Fatty Acids 87:205–208PubMedPubMedCentralGoogle Scholar
  79. 79.
    Litman BJ, Niu S, Polozova A, Mitchell DC (2001) The role of docosahexaenoic acid containing phospholipids in modulating G protein-coupled signaling pathways visual transduction. J Mol Neurosci 16:237–242PubMedGoogle Scholar
  80. 80.
    Guixà-González R, Javanainen M, Gómez-Soler M et al (2016) Membrane omega-3 fatty acids modulate the oligomerisation kinetics of adenosine A2A and dopamine D2 receptors. Sci Rep 22:19839Google Scholar
  81. 81.
    Tuller ER, Beavers CT, Lou JR, Ihnat MA, Benbrook DM, Ding WQ (2009) Docosahexaenoic acid inhibits superoxide dismutase 1 gene transcription in human cancer cells: the involvement of peroxisome proliferator-activated receptor alpha and hypoxia-inducible factor-2alpha signaling. Mol Pharmacol 76:588–595PubMedGoogle Scholar
  82. 82.
    Machová E, Nováková J, Lisá V, Dolezal V (2006) Docosahexaenoic acid supports cell growth and expression of choline acetyltransferase and muscarinic receptors in NG108-15 cell line. J Mol Neurosci 30:25–26PubMedGoogle Scholar
  83. 83.
    Fang IM, Yang CH, Yang CM (2014) Docosahexaenoic acid reduces linoleic acid induced monocyte chemoattractant protein-1 expression via PPARγ and nuclear factor-κB pathway in retinal pigment epithelial cells. Mol Nutr Food Res 58:2053–2065PubMedGoogle Scholar
  84. 84.
    Puskas LG, Kitajka K, Nyakas C, Barcelo-Coblijn G, Farkas T (2003) Short-term administration of omega 3 fatty acids from fish oil results in increased transthyretin transcription in old rat hippocampus. Proc Natl Acad Sci U S A 100:1580–1585PubMedPubMedCentralGoogle Scholar
  85. 85.
    Rojas CV, Martinez JI, Flores I, Hoffman DR, Uauy R (2003) Gene expression analysis in human fetal retinal explants treated with docosahexaenoic acid. Invest Ophthalmol Vis Sci 44:3170–3177PubMedGoogle Scholar
  86. 86.
    Liu BH, Wang YC, Kuo CF, Cheng WM, Shen TF, Ding ST (2005) The effects of docosahexaenoic acid oil and soybean oil on the expression of lipid metabolism related mRNA in pigs. Asian-Australas J Anim Sci 18:1451–1456Google Scholar
  87. 87.
    Zhao G, Etherton TD, Martin KR, Vanden Heuvel JP, Gillies PJ et al (2005) Anti-inflammatory effects of polyunsaturated fatty acids in THP-1 cells. Biochem Biophys Res Commun 336:909–917PubMedGoogle Scholar
  88. 88.
    Calder PC (2006) Polyunsaturated fatty acids and inflammation. Prostaglandins Leukot Essent Fatty Acids 75:197–202PubMedGoogle Scholar
  89. 89.
    Casañas-Sánchez V, Pérez JA, Fabelo N, Quinto-Alemany D, Díaz ML (2015) Docosahexaenoic (DHA) modulates phospholipid-hydroperoxide glutathione peroxidase (Gpx4) gene expression to ensure self-protection from oxidative damage in hippocampal cells. Front Physiol 6:203PubMedPubMedCentralGoogle Scholar
  90. 90.
    Huang CW, Chen YJ, Yang JT, Chen CY, Ajuwon KM, Chen SE, Su NW, Chen YS et al (2017) Docosahexaenoic acid increases accumulation of adipocyte triacylglycerol through up-regulation of lipogenic gene expression in pigs. Lipids Health Dis 16:33PubMedPubMedCentralGoogle Scholar
  91. 91.
    Kitajka K, Puskás LG, Zvara A et al (2002) The role of n-3 polyunsaturated fatty acids in brain: modulation of rat brain gene expression by dietary n-3 fatty acids. Proc Natl Acad Sci U S A 99:2619–2624PubMedPubMedCentralGoogle Scholar
  92. 92.
    Kitajka K, Sinclair AJ, Weisinger RS, Weisinger HS, Mathai M, Jayasooriya AP, Halver JE, Puskas LG (2004) Effects of dietary omega-3 polyunsaturated fatty acids on brain gene expression. Proc Natl Acad Sci U S A 101:10931–10936PubMedPubMedCentralGoogle Scholar
  93. 93.
    Revelli JP, Pescini R, Muzzin P, Seydoux J, Fitzgerald MG, Fraser CM, Giacobino JP (1991) Changes in beta 1- and beta 2-adrenergic receptor mRNA levels in brown adipose tissue and heart of hypothyroid rats. Biochem J 277:625–629PubMedPubMedCentralGoogle Scholar
  94. 94.
    Rubio A, Raasmaja A, Maia AL, Kim KR, Silva JE (1995) Effects of thyroid hormone on norepinephrine signaling in brown adipose tissue. I. Beta 1- and beta 2-adrenergic receptors and cyclic adenosine 3′,5′-monophosphate generation. Endocrinology 136:3267–3276PubMedGoogle Scholar
  95. 95.
    Manzano J, Bernal J, Morte B (2007) Influence of thyroid hormones on maturation of rat cerebellar astrocytes. Int J Dev Neurosci 25:171–179PubMedGoogle Scholar
  96. 96.
    Kirigiti P, Bai Y, Yang YF, Li X, Li B, Brewer G, Machida CA (2001) Agonist-mediated down-regulation of rat beta1-adrenergic receptor transcripts: role of potential post-transcriptional degradation factors. Mol Pharmacol 60:1308–1324PubMedGoogle Scholar
  97. 97.
    Blaxall BC, Pellett AC, Wu SC, Pende A, Port JD (2000) Purification and characterization of beta-adrenergic receptor mRNA-binding proteins. J Biol Chem 274:4290–4297Google Scholar
  98. 98.
    Hosoda K, Fitzgerald LR, Vaidya VA, Feussner GK, Fishman PH, Duman RS (1995) Regulation of beta 2-adrenergic receptor mRNA and gene transcription in rat C6 glioma cells: effects of agonist, forskolin, and protein synthesis inhibition. Mol Pharmacol 48:206–211PubMedGoogle Scholar
  99. 99.
    Serini S, Fasano E, Piccioni E, Monego G, Cittadini ARM, Celleno L, Ranelletti FO, Calviello G (2012) DHA induces apoptosis and differentiation in human melanoma cells in vitro: involvement of HuR-mediated COX-2 mRNA stabilization and β-catenin nuclear translocation. Carcinogenesis 33:164–173PubMedGoogle Scholar
  100. 100.
    Hadcock JR, Malbon CC (1988) Down-regulation of beta-adrenergic receptors: agonist-induced reduction in receptor mRNA levels. Proc Natl Acad Sci U S A 85:5021–5025PubMedPubMedCentralGoogle Scholar
  101. 101.
    Zhu Z, Tan Z, Li Y, Luo H, Hu X, Tang M, Hescheler J, Mu Y et al (2015) Docosahexaenoic acid alters Gsα localization in lipid raft and potentiates adenylate cyclase. Nutrition 31:1025–1030PubMedGoogle Scholar
  102. 102.
    Macia E, Ehrlich M, Massol R, Boucrot E, Brunner C, Kirchhausen T (2006) Dynasore, a cell-permeable inhibitor of dynamin. Dev Cell 10:839–850PubMedGoogle Scholar
  103. 103.
    Hurtado-Lorenzo A, Skinner M, El AJ et al (2006) V-ATPase interacts with ARNO and Arf6 in early endosomes and regulates the protein degradative pathway. Nat Cell Biol 8:124–136PubMedGoogle Scholar
  104. 104.
    van Dam EM, Stoorvogel W (2002) Dynamin-dependent transferrin receptor recycling by endosome-derived clathrin-coated vesicles. Mol Biol Cell 13:169–182PubMedPubMedCentralGoogle Scholar
  105. 105.
    van Dam EM, Ten Broeke T, Jansen K, Spijkers P, Stoorvogel W (2002) Endocytosed transferrin receptors recycle via distinct dynamin and phosphatidylinositol 3-kinase-dependent pathways. J Biol Chem 277:48876–48883PubMedGoogle Scholar
  106. 106.
    Robertson SE, Setty SR, Sitaram A, Marks MS, Lewis RE, Chou MM (2006) Extracellular signal-regulated kinase regulates clathrin-independent endosomal trafficking. Mol Biol Cell 17:645–657PubMedPubMedCentralGoogle Scholar
  107. 107.
    Shenoy SK, Drake MT, Nelson CD, Houtz DA, Xiao K, Madabushi S, Reiter E, Premont RT et al (2006) β-Arrestin-dependent, G protein-independent ERK1/2 activation by the β2 adrenergic receptor. J Biol Chem 281:1261–1273PubMedGoogle Scholar
  108. 108.
    Tohgo A, Choy EW, Gesty-Palmer D, Pierce KL, Laporte S, Oakley RH, Caron MG, Lefkowitz RJ et al (2003) The stability of the G protein-coupled receptor-beta-arrestin interaction determines the mechanism and functional consequence of ERK activation. J Biol Chem 278:6258–6267PubMedGoogle Scholar
  109. 109.
    Luttrell LM, Ferguson SSG, Daaka Y, Miller WE, Maudsley S, Della Rocca GJ, Lin FT, Kawakatsu H et al (1999) β-Arrestin-dependent formation of β2 adrenergic receptor-Src protein kinase complexes. Science 283:655–661PubMedGoogle Scholar
  110. 110.
    Candelario J, Tavakoli H, Chachisvilis M (2012) PTH1 receptor is involved in mediating cellular response to long-chain polyunsaturated fatty acids. PLoS One 7:e52583PubMedPubMedCentralGoogle Scholar
  111. 111.
    Daaka Y, Luttrell LM, Ahn S, Della Rocca GJ, Ferguson SSG, Caron MG, Lefkowitz RJ (1998) Essential role for G protein-coupled receptor endocytosis in the activation of mitogen activated protein kinase. J Biol Chem 273:685–688PubMedGoogle Scholar
  112. 112.
    Vardjan N, Kreft M, Zorec R (2014) Dynamics of β-adrenergic/cAMP signaling and morphological changes in cultured astrocytes. Glia 62:566–579PubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Neurobiology Division, Cell Biology & Physiology DepartmentCSIR-Indian Institute of Chemical BiologyKolkataIndia

Personalised recommendations