Dysfunctional light-evoked regulation of cAMP in photoreceptors and abnormal retinal adaptation in mice lacking dopamine D4 receptors

Izhak Nir, Joseph M. Harrison, Rashidul Haque, Malcolm J. Low, David Grandy, Marcelo Rubinstein, P. Michael Iuvone

    Research output: Contribution to journalArticle

    81 Citations (Scopus)

    Abstract

    Dopamine is a retinal neuromodulator that has been implicated in many aspects of retinal physiology. Photoreceptor cells express dopamine D4 receptors that regulate cAMP metabolism. To assess the effects of dopamine on photoreceptor physiology, we examined the morphology, electrophysiology, and regulation of cAMP metabolism in mice with targeted disruption of the dopamine D4 receptor gene. Photoreceptor morphology and outer segment disc shedding after light onset were normal in D4 knock-out (D4KO) mice. Quinpirole, a dopamine D2/ D3/D4 receptor agonist, decreased cAMP synthesis in retinas of wild-type (WT) mice but not in retinas of D4KO mice. In WT retinas, the photoreceptors of which were functionally isolated by incubation in the presence of exogenous glutamate, light also suppressed cAMP synthesis. Despite the similar inhibition of cAMP synthesis, the effect of light is directly on the photo-receptors and independent of dopamine modulation, because it was unaffected by application of the D4 receptor antagonist L-745,870. Nevertheless, compared with WT retinas, basal cAMP formation was reduced in the photoreceptors of D4KO retinas, and light had no additional inhibitory effect. The results suggest that dopamine, via D4 receptors, normally modulates the cascade that couples light responses to adenylyl cyclase activity in photoreceptor cells, and the absence of this modulation results in dysfunction of the cascade. Dark-adapted electroretinogram (ERG) responses were normal in D4KO mice. However, ERG b-wave responses were greatly suppressed during both light adaptation and early stages of dark adaptation. Thus, the absence of D4 receptors affects adaptation, altering transmission of light responses from photoreceptors to inner retinal neurons. These findings indicate that dopamine D4 receptors normally play a major role in regulating photoreceptor cAMP metabolism and adaptive retinal responses to changing environmental illumination.

    Original languageEnglish (US)
    Pages (from-to)2063-2073
    Number of pages11
    JournalJournal of Neuroscience
    Volume22
    Issue number6
    StatePublished - Mar 15 2002

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    Dopamine D4 Receptors
    Vertebrate Photoreceptor Cells
    Retina
    Light
    Knockout Mice
    Dopamine
    Photoreceptor Cells
    3-((4-(4-chlorophenyl)piperazin-1-yl)methyl)-1H-pyrrolo(2,3-b)pyridine
    Ocular Adaptation
    Quinpirole
    Retinal Neurons
    Dark Adaptation
    Electrophysiology
    Dopamine Receptors
    Lighting
    Adenylyl Cyclases
    Neurotransmitter Agents
    Glutamic Acid
    Genes

    Keywords

    • Adaptation
    • cAMP
    • Dopamine
    • Dopamine D4 receptors
    • Electroretinogram
    • Light adaptation
    • Photoreceptor
    • Retina

    ASJC Scopus subject areas

    • Neuroscience(all)

    Cite this

    Nir, I., Harrison, J. M., Haque, R., Low, M. J., Grandy, D., Rubinstein, M., & Iuvone, P. M. (2002). Dysfunctional light-evoked regulation of cAMP in photoreceptors and abnormal retinal adaptation in mice lacking dopamine D4 receptors. Journal of Neuroscience, 22(6), 2063-2073.

    Dysfunctional light-evoked regulation of cAMP in photoreceptors and abnormal retinal adaptation in mice lacking dopamine D4 receptors. / Nir, Izhak; Harrison, Joseph M.; Haque, Rashidul; Low, Malcolm J.; Grandy, David; Rubinstein, Marcelo; Iuvone, P. Michael.

    In: Journal of Neuroscience, Vol. 22, No. 6, 15.03.2002, p. 2063-2073.

    Research output: Contribution to journalArticle

    Nir, I, Harrison, JM, Haque, R, Low, MJ, Grandy, D, Rubinstein, M & Iuvone, PM 2002, 'Dysfunctional light-evoked regulation of cAMP in photoreceptors and abnormal retinal adaptation in mice lacking dopamine D4 receptors', Journal of Neuroscience, vol. 22, no. 6, pp. 2063-2073.
    Nir, Izhak ; Harrison, Joseph M. ; Haque, Rashidul ; Low, Malcolm J. ; Grandy, David ; Rubinstein, Marcelo ; Iuvone, P. Michael. / Dysfunctional light-evoked regulation of cAMP in photoreceptors and abnormal retinal adaptation in mice lacking dopamine D4 receptors. In: Journal of Neuroscience. 2002 ; Vol. 22, No. 6. pp. 2063-2073.
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