title: The light-activated signaling pathway in SCN-projecting rat retinal ganglion cells.
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.
authors.affiliation: Center for Research on Occupational and Environmental Toxicology, L606, Oregon Health & Science University, 3181 SW Sam Jackson Park Road, Portland, OR 97239, USA.
authors.forename: Erin J
authors.initials: EJ
authors.lastname: Warren
authors.forename: Charles N
authors.initials: CN
authors.lastname: Allen
authors.forename: R Lane
authors.initials: RL
authors.lastname: Brown
authors.forename: David W
authors.initials: DW
authors.lastname: Robinson
mesh_terms: D000818:Animals; D002614:Chelating Agents / Q000494:pharmacology; D054815:Cyclic Nucleotide-Gated Cation Channels; D004305:Dose-Response Relationship, Drug; D004533:Egtazic Acid / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005123:Eye / Q000166:cytology; D019204:GTP-Binding Proteins / Q000494:pharmacology; D007150:Immunohistochemistry / Q000379:methods; D066298:In Vitro Techniques; D007473:Ion Channels / Q000378:metabolism; D008027:Light; D008564:Membrane Potentials / Q000502:physiology / Q000528:radiation effects; D018408:Patch-Clamp Techniques / Q000379:methods; D010775:Photic Stimulation / Q000379:methods; D051381:Rats; D017207:Rats, Sprague-Dawley; D012165:Retinal Ganglion Cells / Q000187:drug effects / Q000502:physiology / Q000528:radiation effects*; D017299:Rod Opsins / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000528:radiation effects*; D013493:Suprachiasmatic Nucleus / Q000502:physiology*; D050052:TRPC Cation Channels / Q000037:antagonists & inhibitors / Q000378:metabolism; D014795:Visual Pathways / Q000502:physiology / Q000528:radiation effects*; D000099210:Melanopsin
chemical_list: D002614:Chelating Agents; D054815:Cyclic Nucleotide-Gated Cation Channels; D004533:Egtazic Acid; D004791:Enzyme Inhibitors; D019204:GTP-Binding Proteins; D007473:Ion Channels; D017299:Rod Opsins; D050052:TRPC Cation Channels; D000099210:Melanopsin