The light-activated signaling pathway in SCN-projecting rat retinal ganglion cells

Authors

  • Erin J. Warren,

    1. Center for Research on Occupational and Environmental Toxicology, L606, Oregon Health & Science University, 3181 SW Sam Jackson Park Road, Portland, OR 97239, USA
    2. Neuroscience Graduate Program and
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  • Charles N. Allen,

    1. Center for Research on Occupational and Environmental Toxicology, L606, Oregon Health & Science University, 3181 SW Sam Jackson Park Road, Portland, OR 97239, USA
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  • R. Lane Brown,

    1. Neurological Sciences Institute, Oregon Health & Science University, 505 NW 185th Avenue, Beaverton, OR 97006, USA
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  • David W. Robinson

    1. Center for Research on Occupational and Environmental Toxicology, L606, Oregon Health & Science University, 3181 SW Sam Jackson Park Road, Portland, OR 97239, USA
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Dr D. W. Robinson, as above.
E-mail: robinsda@ohsu.edu

Abstract

In mammals, the master circadian clock resides in the suprachiasmatic nuclei (SCN) of the hypothalamus. The period and phase of the circadian pacemaker are calibrated by direct photic input from retinal ganglion cells (RGCs). SCN-projecting RGCs respond to light in the absence of rod- and cone-driven synaptic input, a property for which they are termed intrinsically photosensitive. In SCN-projecting RGCs, light activates a nonselective cationic current that displays inward and outward rectification. The goal of the present study was to investigate the identity of the light-activated ion channel and the intracellular signaling pathway leading to its activation. We considered two candidate channels, cyclic nucleotide-gated (CNG) channels and transient receptor potential (TRP) channels, which mediate vertebrate and invertebrate phototransduction, respectively. We report that the intrinsic light response relies upon a G-protein-dependent process. Although our data indicate that cyclic nucleotides modulate the signaling pathway, CNG channels do not appear to conduct the light-activated current because (i) cyclic nucleotides in the pipette solution do not activate a conductance or completely block the light response, (ii) CNG channel blockers fail to inhibit the light response, (iii) the effects of internal and external divalent cations are inconsistent with their effects on CNG channels, and (iv) immunohistochemistry reveals no CNG channels in SCN-projecting RGCs. Finally, we show that the pharmacology of the light-activated channel resembles that of some TRPC channel family members; the response is blocked by lanthanides and ruthenium red and SK&F 96365, and is enhanced by flufenamic acid and 1-oleoyl-2-acetyl-sn-glycerol. Furthermore, immunohistochemical experiments reveal that TRPC6 is expressed in many RGCs, including those that express melanopsin.

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