Cellular and Molecular Neurobiology

, Volume 29, Issue 3, pp 317–328 | Cite as

Activation of Phosphatidylinositol-linked Novel D1 Dopamine Receptor Contributes to the Calcium Mobilization in Cultured Rat Prefrontal Cortical Astrocytes

  • Jue Liu
  • Fang Wang
  • Chao Huang
  • Li-Hong Long
  • Wen-Ning Wu
  • Fei Cai
  • Jiang-Hua Wang
  • Li-Qun Ma
  • Jian-Guo ChenEmail author
Original Paper


Recent evidences indicate the existence of an atypical D1 dopamine receptor other than traditional D1 dopamine receptor in the brain that mediates PI hydrolysis via activation of phospholipase Cβ (PLCβ). To further understand the basic physiological function of this receptor in brain, the effects of a selective phosphoinositide (PI)-linked D1 dopamine receptor agonist SKF83959 on cytosolic free calcium concentration ([Ca2+]i) in cultured rat prefrontal cortical astrocytes were investigated by calcium imaging. The results indicated that SKF83959 caused a transient dose-dependent increase in [Ca2+]i. Application of D1 receptor, but not D2, α1 adrenergic, 5-HT receptor, or cholinergic antagonist prevented SKF83959-induced [Ca2+]i rise, indicating that activation of the D1 dopamine receptor was essential for this response. Increase in [Ca2+]i was a two-step process characterized by an initial increase in [Ca2+]i mediated by release from intracellular stores, supplemented by influx through voltage-gated calcium channels, receptor-operated calcium channels, and capacitative Ca2+ entry. Furthermore, SKF83959-stimulated increase in [Ca2+]i was abolished following treatment with a PLC inhibitor. Overall, these results suggested that activation of D1 receptor by SKF83959 mediates a dose-dependent mobilization of [Ca2+]i via the PLC signaling pathway in cultured rat prefrontal cortical astrocytes.


SKF83959 Dopamine receptor Calcium Astrocyte Phospholipase C 



This work was supported by grants from the National Science Foundation for the Distinguished Young Scientists in China (No. 30425024), the National Basic Research Program of China (973 Program) (No. 2007CB507404), the National Natural Science Foundation of China (No.30570556) to Dr. Jian-Guo Chen, and the Joint Research Fund for Overseas Chinese Young Scholars to Dr. Yong Xia and Dr. Jian-Guo Chen (No. 30728010).


  1. Andringa G, Drukarch B, Leysen JE, Cools AR, Stoof JC (1999a) The alleged dopamine D1 receptor agonist SKF 83959 is a dopamine D1 receptor antagonist in primate cells and interacts with other receptors. Eur J Pharmacol 364:33–41. doi: 10.1016/S0014-2999(98)00825-5 PubMedCrossRefGoogle Scholar
  2. Andringa G, Stoof JC, Cools AR (1999b) Sub-chronic administration of the dopamine D(1) antagonist SKF 83959 in bilaterally MPTP-treated rhesus monkeys: stable therapeutic effects and wearing-off dyskinesia. Psychopharmacology (Berl) 146:328–334. doi: 10.1007/s002130051124 CrossRefGoogle Scholar
  3. Araque A, Carmignoto G, Haydon PG (2001) Dynamic signaling between astrocytes and neurons. Annu Rev Physiol 63:795–813. doi: 10.1146/annurev.physiol.63.1.795 PubMedCrossRefGoogle Scholar
  4. Araque A, Sanzgiri RP, Parpura V, Haydon PG (1998) Calcium elevation in astrocytes causes an NMDA receptor-dependent increase in the frequency of miniature synaptic currents in cultured hippocampal neurons. J Neurosci 18:6822–6829PubMedGoogle Scholar
  5. Arnt J, Hyttel J, Sanchez C (1992) Partial and full dopamine D1 receptor agonists in mice and rats: relation between behavioural effects and stimulation of adenylate cyclase activity in vitro. Eur J Pharmacol 213:259–267. doi: 10.1016/0014-2999(92)90690-6 PubMedCrossRefGoogle Scholar
  6. Barritt GJ (1999) Receptor-activated Ca2+ inflow in animal cells: a variety of pathways tailored to meet different intracellular Ca2+ signalling requirements. Biochem J 337:153–169. doi: 10.1042/0264-6021:3370153 PubMedCrossRefGoogle Scholar
  7. Bezzi P, Carmignoto G, Pasti L, Vesce S, Rossi D, Rizzini BL et al (1998) Prostaglandins stimulate calcium-dependent glutamate release in astrocytes. Nature 391:281–285. doi: 10.1038/34651 PubMedCrossRefGoogle Scholar
  8. Bootman MD, Collins TJ, Peppiatt CM, Prothero LS, MacKenzie L, De Smet P et al (2001) Calcium signaling—an overview. Semin Cell Dev Biol 12:3–10. doi: 10.1006/scdb.2000.0211 PubMedCrossRefGoogle Scholar
  9. Burgos M, Pastor MD, Gonzalez JC, Martinez-Galan JR, Vaquero CF, Fradejas N et al (2007) PKCepsilon upregulates voltage-dependent calcium channels in cultured astrocytes. Glia 55:1437–1448. doi: 10.1002/glia.20555 PubMedCrossRefGoogle Scholar
  10. Carmignoto G, Pasti L, Pozzan T (1998) On the role of voltage-dependent calcium channels incalcium signaling of astrocytes in situ. J Neurosci 18:4637–4645PubMedGoogle Scholar
  11. Chen J, Backus KH, Deitmer JW (1997) Intracellular calcium transients and potassium current oscillations evoked by glutamate in cultured rat astrocytes. J Neurosci 17:7278–7287PubMedGoogle Scholar
  12. Conti F (1997) Localization of NMDA receptors in the cerebral cortex: a schematic overview. Braz J Med Biol Res 30:555–560. doi: 10.1590/S0100-879X1997000500001 PubMedCrossRefGoogle Scholar
  13. D’Ascenzo M, Vairano M, Andreassi C, Navarra P, Azzena GB, Grassi C (2004) Electrophysiological and molecular evidence of L-(Cav1), N-(Cav2.2), and R-(Cav2.3) type Ca2+ channels in rat cortical astrocytes. Glia 45:354–363. doi: 10.1002/glia.10336 PubMedCrossRefGoogle Scholar
  14. Deveney AM, Waddington JL (1995) Pharmacological characterization of behavioural responses to SK&F 83959 in relation to‚ D1-like’ dopamine receptors not linked to adenylyl cyclase. Br J Pharmacol 116:2120–2126PubMedGoogle Scholar
  15. Fan D, Grooms SY, Araneda RC, Johnson AB, Dobrenis K, Kessler JA et al (1999) AMPA receptor protein expression and function in astrocytes cultured from hippocampus. J Neurosci Res 57:557–571. doi:10.1002/(SICI)1097-4547(19990815)57:4<557::AID-JNR16>3.0.CO;2-IPubMedCrossRefGoogle Scholar
  16. Felder CC, Jose PA, Axelrod J (1989) The dopamine-1 agonist, SKF 82526, stimulates phospholipase-C activity independent of adenylate cyclase. J Pharmacol Exp Ther 248:171–175PubMedGoogle Scholar
  17. Friedman E, Jin LQ, Cai GP, Hollon TR, Drago J, Sibley DR et al (1997) D1-like dopaminergic activation of phosphoinositide hydrolysis is independent of D1A dopamine receptors: evidence from D1A knockout mice. Mol Pharmacol 51:6–11PubMedGoogle Scholar
  18. Gnanalingham KK, Hunter AJ, Jenner P, Marsden CD (1995) The differential behavioural effects of benzazepine D1 dopamine agonists with varying efficacies, co-administered with quinpirole in primate and rodent models of Parkinson’s disease. Psychopharmacology (Berl) 117:287–297. doi: 10.1007/BF02246103 CrossRefGoogle Scholar
  19. Goldman-Rakic PS, Selemon LD (1997) Functional and anatomical aspects of prefrontal pathology in schizophrenia. Schizophr Bull 23:437–458PubMedGoogle Scholar
  20. Golovina VA (2005) Visualization of localized store-operated calcium entry in mouse astrocytes. Close proximity to the endoplasmic reticulum. J Physiol 564:737–749. doi: 10.1113/jphysiol.2005.085035 PubMedCrossRefGoogle Scholar
  21. Grimaldi M, Favit A, Alkon DL (1999) cAMP-induced cytoskeleton rearrangement increases calcium transients through the enhancement of capacitative calcium entry. J Biol Chem 274:33557–33564. doi: 10.1074/jbc.274.47.33557 PubMedCrossRefGoogle Scholar
  22. Haydon PG (2001) GLIA: listening and talking to the synapse. Nat Rev Neurosci 2:185–193. doi: 10.1038/35058528 PubMedCrossRefGoogle Scholar
  23. Hu B, Sun SG, Tong ET (2004) NMDA and AMPA receptors mediated intracellular calcium increase in rat cortical astrocytes. Acta Pharmacol Sin 25:714–720PubMedGoogle Scholar
  24. Innocenti B, Parpura V, Haydon PG (2000) Imaging extracellular waves of glutamate during calcium signaling in cultured astrocytes. J Neurosci 20:1800–1808PubMedGoogle Scholar
  25. Jin LQ, Goswami S, Cai G, Zhen X, Friedman E (2003) SKF83959 selectively regulates phosphatidylinositol-linked D1 dopamine receptors in rat brain. J Neurochem 85:378–386. doi: 10.1046/j.1471-4159.2003.01698.x PubMedCrossRefGoogle Scholar
  26. Jung S, Pfeiffer F, Deitmer JW (2000) Histamine-induced calcium entry in rat cerebellar astrocytes: evidence for capacitative and non-capacitative mechanisms. J Physiol 527:549–561. doi: 10.1111/j.1469-7793.2000.00549.x PubMedCrossRefGoogle Scholar
  27. Kinor N, Geffen R, Golomb E, Zinman T, Yadid G (2001) Dopamine increases glial cell line-derived neurotrophic factor in human fetal astrocytes. Glia 33:143–150. doi:10.1002/1098-1136(200102)33:2<143::AID-GLIA1013>3.0.CO;2-3PubMedCrossRefGoogle Scholar
  28. Koizumi S, Fujishita K, Tsuda M, Shigemoto-Mogami Y, Inoue K (2003) Dynamic inhibition of excitatory synaptic transmission by astrocyte-derived ATP in hippocampal cultures. Proc Natl Acad Sci USA 100:11023–11028. doi: 10.1073/pnas.1834448100 PubMedCrossRefGoogle Scholar
  29. Latour I, Hamid J, Beedle AM, Zamponi GW, Macvicar BA (2003) Expression of voltage-gated Ca2+ channel subtypes in cultured astrocytes. Glia 41:347–353. doi: 10.1002/glia.10162 PubMedCrossRefGoogle Scholar
  30. Lee FJ, Xue S, Pei L, Vukusic B, Chery N, Wang Y et al (2002) Dual regulation of NMDA receptor functions by direct protein-protein interactions with the dopamine D1 receptor. Cell 111:219–230. doi: 10.1016/S0092-8674(02)00962-5 PubMedCrossRefGoogle Scholar
  31. Lee HK, Takamiya K, Kameyama K, He K, Yu S, Rossetti L et al (2007) Identification and characterization of a novel phosphorylation site on the GluR1 subunit of AMPA receptors. Mol Cell Neurosci 36:84–96Google Scholar
  32. Lee SP, So CH, Rashid AJ, Varghese G, Cheng R, Lanca AJ et al (2004) Dopamine D1 and D2 receptor co-activation generates a novel phospholipase C-mediated calcium signal. J Biol Chem 279:35671–35678. doi: 10.1074/jbc.M401923200 PubMedCrossRefGoogle Scholar
  33. Lezcano N, Bergson C (2002) D1/D5 dopamine receptors stimulate intracellular calcium release in primary cultures of neocortical and hippocampal neurons. J Neurophysiol 87:2167–2175PubMedGoogle Scholar
  34. Lo KJ, Luk HN, Chin TY, Chueh SH (2002) Store depletion-induced calcium influx in rat cerebellar astrocytes. Br J Pharmacol 135:1383–1392. doi: 10.1038/sj.bjp.0704594 PubMedCrossRefGoogle Scholar
  35. Logan SM, Rivera FE, Leonard JP (1999) Protein kinase C modulation of recombinant NMDA receptor currents: roles for the C-terminal C1 exon and calcium ions. J Neurosci 19:974–986PubMedGoogle Scholar
  36. Ming Y, Zhang H, Long L, Wang F, Chen J, Zhen X (2006) Modulation of Ca2+ signals by phosphatidylinositol-linked novel D1 dopamine receptor in hippocampal neurons. J Neurochem 98:1316–1323. doi: 10.1111/j.1471-4159.2006.03961.x PubMedCrossRefGoogle Scholar
  37. Newman EA, Zahs KR (1998) Modulation of neuronal activity by glial cells in the retina. J Neurosci 18:4022–4028PubMedGoogle Scholar
  38. Newman EA (2003) New roles for astrocytes: regulation of synaptic transmission. Trends Neurosci 26:536–542. doi: 10.1016/S0166-2236(03)00237-6 PubMedCrossRefGoogle Scholar
  39. Pacheco MA, Jope RS (1997) Comparison of [3H]phosphatidylinositol and [3H]phosphatidylinositol 4, 5-bisphosphate hydrolysis in postmortem human brain membranes and characterization of stimulation by dopamine D1 receptors. J Neurochem 69:639–644PubMedGoogle Scholar
  40. Panchalingam S, Undie AS (2001) SKF83959 exhibits biochemical agonism by stimulating [(35)S]GTP gamma S binding and phosphoinositide hydrolysis in rat and monkey brain. Neuropharmacology 40:826–837. doi: 10.1016/S0028-3908(01)00011-9 PubMedCrossRefGoogle Scholar
  41. Panchalingam S, Undie AS (2005) Physicochemical modulation of agonist-induced [35 s]GTPgammaS binding: implications for coexistence of multiple functional conformations of dopamine D1-like receptors. J Recept Signal Transduct Res 25:125–146. doi: 10.1080/10799890500184948 PubMedCrossRefGoogle Scholar
  42. Parpura V, Basarsky TA, Liu F, Jeftinija K, Jeftinija S, Haydon PG (1994) Glutamate-mediated astrocyte-neuron signalling. Nature 369:744–747. doi: 10.1038/369744a0 PubMedCrossRefGoogle Scholar
  43. Parpura V, Haydon PG (2000) Physiological astrocytic calcium levels stimulate glutamate release to modulate adjacent neurons. Proc Natl Acad Sci USA 97:8629–8634. doi: 10.1073/pnas.97.15.8629 PubMedCrossRefGoogle Scholar
  44. Pasti L, Volterra A, Pozzan T, Carmignoto G (1997) Intracellular calcium oscillations in astrocytes: a highly plastic, bidirectional form of communication between neurons and astrocytes in situ. J Neurosci 17:7817–7830PubMedGoogle Scholar
  45. Perea G, Araque A (2007) Astrocytes potentiate transmitter release at single hippocampal synapses. Science 317:1083–1086. doi: 10.1126/science.1144640 PubMedCrossRefGoogle Scholar
  46. Rashid AJ, So CH, Kong MM, Furtak T, El-Ghundi M, Cheng R et al (2007) D1–D2 dopamine receptor heterooligomers with unique pharmacology are coupled to rapid activation fo Gq/11on the striatum. Proc Natl Acad Sci USA 104:654–659. doi: 10.1073/pnas.0604049104 PubMedCrossRefGoogle Scholar
  47. Reuss B, Leung DS, Ohlemeyer C, Kettenmann H, Unsicker K (2000) Regionally distinct regulation of astroglial neurotransmitter receptors by fibroblast growth factor-2. Mol Cell Neurosci 16:42–58. doi: 10.1006/mcne.2000.0857 PubMedCrossRefGoogle Scholar
  48. Reuss B, Lorenzen A, Unsicker K (2001) Dopamine and epinephrine, but not serotonin, downregulate dopamine sensitivity in cultured cortical and striatal astroglial cells. Receptors Channels 7:441–451PubMedGoogle Scholar
  49. Schipke CG, Ohlemeyer C, Matyash M, Nolte C, Kettenmann H, Kirchhoff F (2001) Astrocytes of the mouse neocortex express functional N-methyl-D-aspartate receptors. FASEB J 15:1270–1272PubMedGoogle Scholar
  50. Sontheimer H (1994) Voltage-dependent ion channels in glial cells. Glia 11:156–172. doi: 10.1002/glia.440110210 PubMedCrossRefGoogle Scholar
  51. Tang TS, Bezprozvanny I (2004) Dopamine receptor- mediated Ca2+ signaling in striatal medium spiny neurons. J Biol Chem 279:42082–42094. doi: 10.1074/jbc.M407389200 PubMedCrossRefGoogle Scholar
  52. Taylor CW (2002) Controlling calcium entry. Cell 111:767–769. doi: 10.1016/S0092-8674(02)01197-2 PubMedCrossRefGoogle Scholar
  53. Tingley WG, Roche KW, Thompson AK, Huganir RL (1993) Regulation of NMDA receptor phosphorylation by alternative splicing of the C-terminal domain. Nature 364:70–73. doi: 10.1038/364070a0 PubMedCrossRefGoogle Scholar
  54. Undie AS, Weinstock J, Sarau HM, Friedman E (1994) Evidence for a distinct D1-like dopamine receptor that couples to activation of phosphoinositide metabolism in brain. J Neurochem 62:2045–2048PubMedCrossRefGoogle Scholar
  55. Van Bockstaele EJ, Colago EE (1996) Selective distribution of the NMDA-R1 glutamate receptor in astrocytes and presynaptic axon terminals in the nucleus locus coeruleus of the rat brain: an immunoelectron microscopic study. J Comp Neurol 369:483–496. doi:10.1002/(SICI)1096-9861(19960610)369:4<483::AID-CNE1>3.0.CO;2-0PubMedCrossRefGoogle Scholar
  56. Waddington JL, O’Tuathaigh C, O’Sullivan G, Tomiyama K, Koshikawa N, Croke DT (2005) Phenotypic studies on dopamine receptor subtype and associated signal transduction mutants: insights and challenges from 10 years at the psychopharmacology-molecular biology interface. Psychopharmacology (Berl) 181:611–638. doi: 10.1007/s00213-005-0058-8 CrossRefGoogle Scholar
  57. Wirtshafter D, Osborn CV (2005) The atypical dopamine D1 receptor agonist SKF 83959 induces striatal Fos expression in rats. Eur J Pharmacol 528:88–94. doi: 10.1016/j.ejphar.2005.11.003 PubMedCrossRefGoogle Scholar
  58. Yang CR, Chen L (2005) Targeting prefrontal cortical dopamine D1 and N-methyl-D-aspartate receptor interactions in schizophrenia treatment. Neuroscientist 11:452–470. doi: 10.1177/1073858405279692 PubMedCrossRefGoogle Scholar
  59. Yu PY, Eisner GM, Yamaguchi I, Mouradian MM, Felder RA, Jose PA (1996) Dopamine D1A receptor regulation of phospholipase C isoform. J Biol Chem 271:19503–19508. doi: 10.1074/jbc.271.32.19503 PubMedCrossRefGoogle Scholar
  60. Zanassi P, Paolillo M, Montecucco A, Avvedimento EV, Schinelli S (1999) Pharmacological and molecular evidence for dopamine D(1) receptor expression by striatal astrocytes in culture. J Neurosci Res 58:544–552. doi:10.1002/(SICI)1097-4547(19991115)58:4<544::AID-JNR7>3.0.CO;2-9PubMedCrossRefGoogle Scholar
  61. Zhang H, Ma L, Wang F, Chen J, Zhen X (2007) Chronic SKF83959 induced less severe dyskinesia and attenuated L-DOPA-induced dyskinesia in 6-OHDA-lesioned rat model of Parkinson’s disease. Neuropharmacology 53:125–133. doi: 10.1016/j.neuropharm.2007.04.004 PubMedCrossRefGoogle Scholar
  62. Zhen X, Goswami S, Friedman E (2005) The role of the phosphatidyinositol-linked D1 dopamine receptor in the pharmacology of SKF83959. Pharmacol Biochem Behav 80:597–601. doi: 10.1016/j.pbb.2005.01.016 PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2008

Authors and Affiliations

  • Jue Liu
    • 1
  • Fang Wang
    • 1
    • 2
    • 3
  • Chao Huang
    • 1
  • Li-Hong Long
    • 1
    • 2
    • 3
  • Wen-Ning Wu
    • 1
  • Fei Cai
    • 1
  • Jiang-Hua Wang
    • 1
  • Li-Qun Ma
    • 1
  • Jian-Guo Chen
    • 1
    • 2
    • 3
    Email author
  1. 1.Department of Pharmacology, Tongji Medical CollegeHuazhong University of Science and TechnologyWuhanChina
  2. 2.Key Laboratory of Neurological Diseases (HUST)Ministry of Education of ChinaWuhanChina
  3. 3.Hubei Key Laboratory of Neurological Diseases (HUST)WuhanChina

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