title: A key role for cyclic nucleotide gated (CNG) channels in cGMP-related retinitis pigmentosa.
abstract: The rd1 natural mutant is one of the first and probably the most commonly studied mouse model for retinitis pigmentosa (RP), a severe and frequently blinding human retinal degeneration. In several decades of research, the link between the increase in photoreceptor cGMP levels and the extremely rapid cell death gave rise to a number of hypotheses. Here, we provide clear evidence that the presence of cyclic nucleotide gated (CNG) channels in the outer segment membrane is the key to rod photoreceptor loss. In Cngb1(-/-) × rd1 double mutants devoid of regular CNG channels, cGMP levels are still pathologically high, but rod photoreceptor viability and outer segment morphology are greatly improved. Importantly, cone photoreceptors, the basis for high-resolution daylight and colour vision, survived and remained functional for extended periods of time. These findings strongly support the hypothesis of deleterious calcium (Ca(2+))-influx as the cause of rapid rod cell death and highlight the importance of CNG channels in this process. Furthermore, our findings suggest that targeting rod CNG channels, rather than general Ca(2+)-channel blockade, is a most promising symptomatic approach to treat otherwise incurable forms of cGMP-related RP.
authors.affiliation: Division of Experimental Ophthalmology, Institute for Ophthalmic Research, University of Tübingen, Röntgenweg 11, 72076 Tübingen, Germany. francois.paquet-durand@klinikum.unituebingen.de
authors.forename: François
authors.initials: F
authors.lastname: Paquet-Durand
authors.forename: Susanne
authors.initials: S
authors.lastname: Beck
authors.forename: Stylianos
authors.initials: S
authors.lastname: Michalakis
authors.forename: Tobias
authors.initials: T
authors.lastname: Goldmann
authors.forename: Gesine
authors.initials: G
authors.lastname: Huber
authors.forename: Regine
authors.initials: R
authors.lastname: Mühlfriedel
authors.forename: Dragana
authors.initials: D
authors.lastname: Trifunović
authors.forename: M Dominik
authors.initials: MD
authors.lastname: Fischer
authors.forename: Edda
authors.initials: E
authors.lastname: Fahl
authors.forename: Gabriele
authors.initials: G
authors.lastname: Duetsch
authors.forename: Elvir
authors.initials: E
authors.lastname: Becirovic
authors.forename: Uwe
authors.initials: U
authors.lastname: Wolfrum
authors.forename: Theo
authors.initials: T
authors.lastname: van Veen
authors.forename: Martin
authors.initials: M
authors.lastname: Biel
authors.forename: Naoyuki
authors.initials: N
authors.lastname: Tanimoto
authors.forename: Mathias W
authors.initials: MW
authors.lastname: Seeliger
mesh_terms: D000818:Animals; D002118:Calcium / Q000378:metabolism; D006152:Cyclic GMP / Q000378:metabolism*; D054815:Cyclic Nucleotide-Gated Cation Channels / Q000235:genetics / Q000378:metabolism*; D004195:Disease Models, Animal; D005260:Female; D006801:Humans; D008297:Male; D051379:Mice; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D017948:Retinal Rod Photoreceptor Cells / Q000378:metabolism; D012174:Retinitis Pigmentosa / Q000235:genetics / Q000378:metabolism*
chemical_list: C529481:Cngb1 protein, mouse; D054815:Cyclic Nucleotide-Gated Cation Channels; D009419:Nerve Tissue Proteins; D006152:Cyclic GMP; D002118:Calcium