Skip to main content
SpringerLink
Log in

Dopamine D2 Receptor-Mediated Modulation of Rat Retinal Ganglion Cell Excitability

  • Original Article
  • Published:
Neuroscience Bulletin Aims and scope Submit manuscript

Abstract

Ganglion cells (RGCs) are the sole output neurons of the retinal circuity. Here, we investigated whether and how dopamine D2 receptors modulate the excitability of dissociated rat RGCs. Application of the selective D2 receptor agonist quinpirole inhibited outward K+ currents, which were mainly mediated by glybenclamide- and 4-aminopyridine-sensitive channels, but not the tetraethylammonium-sensitive channel. In addition, quinpirole selectively enhanced Nav1.6 voltage-gated Na+ currents. The intracellular cAMP/protein kinase A, Ca2+/calmodulin-dependent protein kinase II, and mitogen-activated protein kinase/extracellular signal-regulated kinase signaling pathways were responsible for the effects of quinpirole on K+ and Na+ currents, while phospholipase C/protein kinase C signaling was not involved. Under current-clamp conditions, the number of action potentials evoked by positive current injection was increased by quinpirole. Our results suggest that D2 receptor activation increases RGC excitability by suppressing outward K+ currents and enhancing Nav1.6 currents, which may affect retinal visual information processing.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7
Fig. 8

Similar content being viewed by others

References

  1. Barros M, Mello EL, Huston JP, Tomaz C. Behavioral effects of buspirone in the marmoset employing a predator confrontation test of fear and anxiety. Pharmacol Biochem Behav 2001, 68: 255–262.

    Article  CAS  PubMed  Google Scholar 

  2. Bissiere S, Humeau Y, Luthi A. Dopamine gates LTP induction in lateral amygdala by suppressing feedforward inhibition. Nat Neurosci 2003, 6: 587–592.

    Article  CAS  PubMed  Google Scholar 

  3. Missale C, Nash SR, Robinson SW, Jaber M, Caron MG. Dopamine receptors: From structure to function. Physiol Rev 1998, 78: 189–225.

    Article  CAS  PubMed  Google Scholar 

  4. Paspalas CD, Goldman-Rakic PS. Presynaptic D1 dopamine receptors in primate prefrontal cortex: Target-specific expression in the glutamatergic synapse. J Neurosci 2005, 25: 1260–1267.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Yang CR, Seamans JK. Dopamine D1 receptor actions in layers V-VI rat prefrontal cortex neurons in vitro: Modulation of dendritic-somatic signal integration. J Neurosci 1996, 16: 1922–1935.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Wang ZY, Liang SX, Yu SS, Xie T, Wang BC, Wang JK, et al. Distinct roles of dopamine receptors in the lateral thalamus in a rat model of decisional impulsivity. Neurosci Bull 2017, 33: 413–422.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  7. Enjalbert A, Bockaert J. Pharmacological characterization of the D2 dopamine receptor negatively coupled with adenylate-cyclase in rat anterior pituitary. Mol Pharmacol 1983, 23: 576–584.

    CAS  PubMed  Google Scholar 

  8. Sibley DR, Monsma FJ Jr. Molecular-biology of dopamine-receptors. Trends Pharmacol Sci 1992, 13: 61–69.

    Article  CAS  PubMed  Google Scholar 

  9. Beaulieu JM, Espinoza S, Gainetdinov RR. Dopamine receptors - IUPHAR Review 13. Br J Pharmacol 2015, 172: 1–23.

    Article  CAS  PubMed  Google Scholar 

  10. Jackson CR, Ruan GX, Aseem F, Abey J, Gamble K, Stanwood G, et al. Retinal dopamine mediates multiple dimensions of light-adapted vision. J Neurosci 2012, 32: 9359–9368.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Lavoie J, Illiano P, Sotnikova TD, Gainetdinov RR, Beaulieu JM, Hebert M. The electroretinogram as a biomarker of central dopamine and serotonin: Potential relevance to psychiatric disorders. Biol Psychiat 2014, 75: 479–486.

    Article  CAS  PubMed  Google Scholar 

  12. Witkovsky P. Dopamine and retinal function. Doc Ophthalmol 2004, 108: 17–40.

    Article  PubMed  Google Scholar 

  13. Gustincich S, Feigenspan A, Wu DK, Koopman LJ, Raviola E. Control of dopamine release in the retina: A transgenic approach to neural networks. Neuron 1997, 18: 723–736.

    Article  CAS  PubMed  Google Scholar 

  14. Hokoc JN, Mariani AP. Tyrosine–hydroxylase immunoreactivity in the rhesus-monkey retina reveals synapses from bipolar cells to dopaminergic amacrine cells. J Neurosci 1987, 7: 2785–2793.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Pourcho RG. Dopaminergic amacrine cells in the cat retina. Brain Res 1982, 252: 101–109.

    Article  CAS  PubMed  Google Scholar 

  16. Thier P, Alder V. Action of iontophoretically applied dopamine on cat retinal ganglion cells. Brain Res 1984, 292: 109–121.

    Article  CAS  PubMed  Google Scholar 

  17. Hayashida Y, Ishida AT. Dopamine receptor activation can reduce voltage-gated Na+ current by modulating both entry into and recovery from inactivation. J Neurophysiol 2004, 92: 3134–3141.

    Article  CAS  PubMed  Google Scholar 

  18. Hayashida Y, Rodriguez CV, Ogata G, Partida GJ, Oi H, Stradleigh TW, et al. Inhibition of adult rat retinal ganglion cells by D-1-type dopamine receptor activation. J Neurosci 2009, 29: 15001–15016.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Ogata G, Stradleigh TW, Partida GJ, Ishida AT. Dopamine and full-field illumination activate D1 and D2-D5-type receptors in adult rat retinal ganglion cells. J Comp Neurol 2012, 520: 4032–4049.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Vaquero CF, Pignatelli A, Partida GJ, Ishida AT. A dopamine- and protein kinase A-dependent mechanism for network adaptation in retinal ganglion cells. J Neurosci 2001, 21: 8624–8635.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Tran VT, Dickman M. Differential localization of dopamine D1-receptors and D2 receptors in rat retina. Invest Ophthalmol Vis Sci 1992, 33: 1620–1626.

    CAS  PubMed  Google Scholar 

  22. Wagner HJ, Luo BG, Ariano MA, Sibley DR, Stell WK. Localization of D2 dopamine-receptors in vertebrate retinae with anti-peptide antibodies. J Comp Neurol 1993, 331: 469–481.

    Article  CAS  PubMed  Google Scholar 

  23. Akopian AN, Sivilotti L, Wood JN. A tetrodotoxin-resistant voltage-gated sodium channel expressed by sensory neurons. Nature 1996, 379: 257–262.

    Article  CAS  PubMed  Google Scholar 

  24. Ettaiche M, Heurteaux C, Blondeau N, Borsotto M, Tinel N, Lazdunski M. ATP-sensitive potassium channels (K-ATP) in retina: a key role for delayed ischemic tolerance. Brain Res 2001, 890: 118–129.

    Article  CAS  PubMed  Google Scholar 

  25. Fjell J, DibHajj S, Fried K, Black JA, Waxman SG. Differential expression of sodium channel genes in retinal ganglion cells. Mol Brain Res 1997, 50: 197–204.

    Article  CAS  PubMed  Google Scholar 

  26. Koeberle PD, Wang Y, Schlichter LC. Kv1.1 and Kv1.3 channels contribute to the degeneration of retinal ganglion cells after optic nerve transection in vivo. Cell Death Differ 2010, 17: 134–144.

    Article  CAS  Google Scholar 

  27. Van Wart A, Matthews G. Expression of sodium channels Na(v)1.2 and Na(v)1.6 during postnatal development of the retina. Neurosci Lett 2006, 403: 315–317.

  28. Chen L, Yang XL. Hyperpolarization–activated cation current is involved in modulation of the excitability of rat retinal ganglion cells by dopamine. Neuroscience 2007, 150: 299–308.

    Article  CAS  PubMed  Google Scholar 

  29. Li Q, Wu N, Cui P, Gao F, Qian WJ, Miao Y, et al. Suppression of outward K(+) currents by activating dopamine D1 receptors in rat retinal ganglion cells through PKA and CaMKII signaling pathways. Brain Res 2016, 1635: 95–104.

    Article  CAS  PubMed  Google Scholar 

  30. Cui P, Li XY, Zhao Y, Li Q, Gao F, Li LZ, et al. Activation of dopamine D1 receptors enhances the temporal summation and excitability of rat retinal ganglion cells. Neuroscience 2017, 355: 71–83.

    Article  CAS  PubMed  Google Scholar 

  31. Aizman O, Brismar H, Uhlen P, Zettergren E, Levey AI, Forssberg H, et al. Anatomical and physiological evidence for D1 and D2 dopamine receptor colocalization in neostriatal neurons. Nat Neurosci 2000, 3: 226–230.

    Article  CAS  PubMed  Google Scholar 

  32. Hu XT, Dong Y, Zhang XF, White FJ. Dopamine D2 receptor-activated Ca2+ signaling modulates voltage-sensitive sodium currents in rat nucleus accumbens neurons. J Neurophysiol 2005, 93: 1406–1417.

    Article  CAS  PubMed  Google Scholar 

  33. Maurice N, Mercer J, Chan CS, Hernandez-Lopez S, Held J, Tkatch T, et al. D2 dopamine receptor-mediated modulation of voltage-dependent Na+ channels reduces autonomous activity in striatal cholinergic interneurons. J Neurosci 2004, 24: 10289–10301.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Ramanathan S, Tkatch T, Atherton JF, Wilson CJ, Bevan MD. D2-like dopamine receptors modulate SKCa channel function in subthalamic nucleus neurons through inhibition of Cav2.2 channels. J Neurophysiol 2008, 99: 442–459.

    Article  CAS  PubMed  Google Scholar 

  35. Chen XY, Xue B, Wang J, Liu HX, Shi LM, Xie JX. Potassium channels: a potential therapeutic target for Parkinson’s disease. Neurosci Bull 2018, 34: 341–348.

    Article  CAS  PubMed  Google Scholar 

  36. Valdes-Baizabal C, Soto E, Vega R. Dopaminergic modulation of the voltage-gated sodium current in the cochlear afferent neurons of the rat. PLoS One 2015, 10: e0120808.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  37. Dong LD, Gao F, Wang XH, Miao Y, Wang SY, Wu Y, et al. GluA2 trafficking is involved in apoptosis of retinal ganglion cells induced by activation of EphB/EphrinB reverse signaling in a rat chronic ocular hypertension model. J Neurosci 2015, 35: 5409–5421.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Qian WJ, Yin N, Gao F, Miao Y, Li Q, Li F, et al. Cannabinoid CB1 and CB2 receptors differentially modulate L- and T-type Ca2+ channels in rat retinal ganglion cells. Neuropharmacology 2017, 124: 143–156.

    Article  CAS  PubMed  Google Scholar 

  39. Gao F, Li F, Miao Y, Xu LJ, Zhao Y, Li Q, et al. Involvement of the MEK-ERK/p38-CREB/c-fos signaling pathway in Kir channel inhibition-induced rat retinal Müller cell gliosis. Sci Rep 2017, 7: 1480.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  40. Li LZ, Yin N, Li XY, Miao Y, Cheng S, Li F, et al. Rac1 modulates excitatory synaptic transmission in mouse retinal ganglion cells. Neurosci Bull 2019, 35: 673–687.

    PubMed  PubMed Central  Google Scholar 

  41. Jensen R. Effects of dopamine d2-like receptor antagonists on light responses of ganglion cells in wild-type and P23H rat retinas. PLoS One 2015, 10: e0146154.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  42. Bofill-Cardona E, Kudlacek O, Yang Q, Ahorn H, Freissmuth M, Nanoff C. Binding of calmodulin to the D-2-dopamine receptor reduces receptor signaling by arresting the G protein activation switch. J Biol Chem 2000, 275: 32672–32680.

    Article  CAS  PubMed  Google Scholar 

  43. Liu XY, Chu XP, Mao LM, Wang M, Lan HX, Li MH, et al. Modulation of D2R-NR2B interactions in response to cocaine. Neuron 2006, 52: 897–909.

    Article  CAS  PubMed  Google Scholar 

  44. Fohlmeister JF. Voltage gating by molecular subunits of Na+ and K+ ion channels: higher-dimensional cubic kinetics, rate constants, and temperature. J Neurophysiol 2015, 113: 3759–3777.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Mojumder DK, Frishman LJ, Otteson DC, Sherry DM. Voltage-gated sodium channel alpha-subunits Na(v)1.1, Na(v)1.2, and Na(v)1.6 in the distal mammalian retina. Mol Vis 2007, 13: 2163–2182.

  46. Bosmans F, Rash L, Zhu SY, Diochot S, Lazdunski M, Escoubas P, et al. Four novel tarantula toxins as selective modulators of voltage-gated sodium channel subtypes. Mol Pharmacol 2006, 69: 419–429.

    Article  CAS  PubMed  Google Scholar 

  47. Rosker C, Lohberger B, Hofer D, Steinecker B, Quasthoff S, Schreibmayer W. The TTX metabolite 4,9-anhydro-TTX is a highly specific blocker of the Na-v1.6 voltage-dependent sodium channel. Am J Physiol Cell Physiol 2007, 293: C783–C789.

    Article  CAS  PubMed  Google Scholar 

  48. Saito M, Murai Y, Sato H, Bae YC, Akaike T, Takada M, et al. Two opposing roles of 4-AP-sensitive K+ current in initiation and invasion of spikes in rat mesencephalic trigeminal neurons. J Neurophysiol 2006, 96: 1887–1901.

    Article  CAS  PubMed  Google Scholar 

  49. Wu RL, Barish ME. Modulation of a slowly inactivating potassium current, I-D, by metabotropic glutamate receptor activation in cultured hippocampal pyramidal neurons. J Neurosci 1999, 19: 6825–6837.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Wilke RA, Hsu SF, Jackson MB. Dopamine D4 receptor mediated inhibition of potassium current in neurohypophysial nerve terminals. J Pharmacol Exp Ther 1998, 284: 542–548.

    CAS  PubMed  Google Scholar 

  51. Govindaiah G, Wang Y, Cox CL. Dopamine enhances the excitability of somatosensory thalamocortical neurons. Neuroscience 2010, 170: 981–991.

    Article  CAS  PubMed  Google Scholar 

  52. Perez MF, White FJ, Hu XT. Dopamine D2 receptor modulation of K+ channel activity regulates excitability of nucleus accumbens neurons at different membrane potentials. J Neurophysiol 2006, 96: 2217–2228.

    Article  CAS  PubMed  Google Scholar 

  53. Uchida S, Akaike N, Nabekura J. Dopamine activates inward rectifier K+ channel in acutely dissociated rat substantia nigra neurones. Neuropharmacology 2000, 39: 191–201.

    Article  CAS  PubMed  Google Scholar 

  54. Zhong LR, Artinian L, Rehder V. Dopamine suppresses neuronal activity of helisoma B5 neurons via a D2-Like receptor, activating PLC and K channels. Neuroscience 2013, 228: 109–119.

    Article  CAS  PubMed  Google Scholar 

  55. Lin YJ, Greif GJ, Freedman JE. Multiple sulfonylurea-sensitive potassium channels - a novel subtype modulated by dopamine. Mol Pharmacol 1993, 44: 907–910.

    CAS  PubMed  Google Scholar 

  56. Einhorn LC, Gregerson KA, Oxford GS. D2 dopamine receptor activation of potassium channels inidentified rat lactotrophs - whole-cell and single-channel recording. J Neurosci 1991, 11: 3727–3737.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Hicks GA, Henderson G. Lack of evidence for coupling of the dopamine D2 receptor to an adenosine triphosphate-sensitive potassium (ATP-K+) channel in dopaminergic neurones of the rat substantia nigra. Neurosci Lett 1992, 141: 213–217.

    Article  CAS  PubMed  Google Scholar 

  58. Catterall WA, Goldin AL, Waxman SG. International union of pharmacology. XLVII. nomenclature and structure-function relationships of voltage-gated sodium channels. Pharmacol Rev 2005, 57: 397–409.

    Article  CAS  PubMed  Google Scholar 

  59. Black JA, Waxman SG. Noncanonical roles of voltage-gated sodium channels. Neuron 2013, 80: 280–291.

    Article  CAS  PubMed  Google Scholar 

  60. Catterall WA. From ionic currents to molecular mechanisms: The structure and function of voltage-gated sodium channels. Neuron 2000, 26: 13–25.

    Article  CAS  PubMed  Google Scholar 

  61. Catterall WA. Forty years of sodium channels: structure, function, pharmacology, and epilepsy. Neurochem Res 2017, 42: 2495–2504.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Centonze D, Bracci E, Pisani A, Gubellini P, Bernardi G, Calabresi P. Activation of dopamine D1-like receptors excites LTS interneurons of the striatum. Eur J Neurosci 2002, 15: 2049–2052.

    Article  PubMed  Google Scholar 

  63. Rosenkranz JA, Johnston D. State-dependent modulation of amygdala inputs by dopamine-induced enhancement of sodium currents in layer V entorhinal cortex. J Neurosci 2007, 27: 7054–7069.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Fein AJ, Meadows LS, Chen C, Slat EA, Isom LL. Cloning and expression of a zebrafish SCN1B ortholog and identification of a species-specific splice variant. BMC Genomics 2007, 8: 226.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  65. Kaplan MR, Cho MH, Ullian EM, Isom LL, Levinson SR, Barres BA. Differential control of clustering of the sodium channels Na(v)1.2 and Na(v)1.6 at developing CNS nodes of Ranvier. Neuron 2001, 30: 105–119.

    Article  CAS  PubMed  Google Scholar 

  66. Cho DI, Zheng M, Kim KM. Current perspectives on the selective regulation of dopamine D2 and D3 receptors. Arch Pharm Res 2010, 33: 1521–1538.

    Article  CAS  PubMed  Google Scholar 

  67. Higley MJ, Sabatini BL. Competitive regulation of synaptic Ca2+ influx by D2 dopamine and A2A adenosine receptors. Nat Neurosci 2010, 13: 958–966.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Cussac D, Newman-Tancredi A, Pasteau V, Millan MJ. Human dopamine D3 receptors mediate mitogen- activated protein kinase activation via a phosphatidylinositol 3-kinase and an atypical protein kinase C-dependent mechanism. Mol Pharmacol 1999, 56: 1025–1030.

    Article  CAS  PubMed  Google Scholar 

  69. Hernandez-Lopez S, Tkatch T, Perez-Garci E, Galarraga E, Bargas J, Hamm H, et al. D2 dopamine receptors in striatal medium spiny neurons reduce L-type Ca2+ currents and excitability via a novel PLC[beta]1-IP3-calcineurin-signaling cascade. J Neurosci 2000, 20: 8987–8995.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Gupta SK, Mishra RK. The effect of dopamine-D1 and dopamine-D2 receptor agonists on inositol phosphate turnover in rat striatal slices. Biochem Int 1990, 22: 887–894.

    CAS  PubMed  Google Scholar 

  71. Hille B. Potassium channels and chloride channels. In: Hille B (Ed.). Ion Channels of Excitable Membrane. Sunderland: Sinauer Associates, Inc. 2001: 131–167.

    Google Scholar 

  72. Yang CR, Mogenson GJ. Dopamine enhances terminal excitability of hippocampal accumbens neurons via D2 receptor: role of dopamine in presynaptic inhibition. J Neurosci 1986, 6: 2470–2478.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Li Q, Cui P, Miao Y, Gao F, Li XY, Qian WJ, et al. Activation of group I metabotropic glutamate receptors regulates the excitability of rat retinal ganglion cells by suppressing Kir and I (h). Brain Struct Funct 2017, 222: 813–830.

    Article  CAS  PubMed  Google Scholar 

  74. Aung MH, Park HN, Han MK, Obertone TS, Abey J, Aseem F, et al. Dopamine deficiency contributes to early visual dysfunction in a rodent model of type 1 diabetes. J Neurosci 2014, 34: 726–736.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Kitaoka Y, Kumai T. Modulation of retinal dopaminergic cells by nitric oxide. A protective effect on NMDA-induced retinal injury. In Vivo 2004, 18: 311–315.

  76. Nishimura C, Kuriyama K. Alterations in the retinal dopaminergic neuronal system in rats with streptozotocin-induced diabetes. J Neurochem 1985, 45: 448–455.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

We thank Dr. Xiong-Li Yang for helpful discussion and critical comments on the manuscript. This work was supported by grants from the National Natural Science Foundation of China (31671078, 81790642, and 31872765), the Shanghai Municipal Science and Technology Major Project (No.2018SHZDZX01) and ZJ Lab.

Author information

Author notes

  1. Ning Yin and Yu-Long Yang have contributed equally to this work.

Authors and Affiliations

  1. Department of Neurology, State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science, Institutes of Brain Science, Zhongshan Hospital, Fudan University, Shanghai, 200032, China

    Ning Yin, Yu-Long Yang, Shuo Cheng, Hong-Ning Wang, Xin Hu, Yanying Miao, Fang Li & Zhongfeng Wang

Authors
  1. Ning Yin
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Yu-Long Yang
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Shuo Cheng
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Hong-Ning Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Xin Hu
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Yanying Miao
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Fang Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Zhongfeng Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Zhongfeng Wang.

Ethics declarations

Conflict of interest

The authors declare no potential conflict of interest.

Electronic supplementary material

Below is the link to the electronic supplementary material.

Supplementary material 1 (PDF 376 kb)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Yin, N., Yang, YL., Cheng, S. et al. Dopamine D2 Receptor-Mediated Modulation of Rat Retinal Ganglion Cell Excitability. Neurosci. Bull. 36, 230–242 (2020). https://doi.org/10.1007/s12264-019-00431-3

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12264-019-00431-3

Keywords

Search

Navigation