title: Loss of HCN1 enhances disease progression in mouse models of CNG channel-linked retinitis pigmentosa and achromatopsia.
abstract: Most inherited blinding diseases are characterized by compromised retinal function and progressive degeneration of photoreceptors. However, the factors that affect the life span of photoreceptors in such degenerative retinal diseases are rather poorly understood. Here, we explore the role of hyperpolarization-activated cyclic nucleotide-gated channel 1 (HCN1) in this context. HCN1 is known to adjust retinal function under mesopic conditions, and although it is expressed at high levels in rod and cone photoreceptor inner segments, no association with any retinal disorder has yet been found. We investigated the effects of an additional genetic deletion of HCN1 on the function and survival of photoreceptors in a mouse model of CNGB1-linked retinitis pigmentosa (RP). We found that the absence of HCN1 in Cngb1 knockout (KO) mice exacerbated photoreceptor degeneration. The deleterious effect was reduced by expression of HCN1 using a viral vector. Moreover, pharmacological inhibition of HCN1 also enhanced rod degeneration in Cngb1 KO mice. Patch-clamp recordings revealed that the membrane potentials of Cngb1 KO and Cngb1/Hcn1 double-KO rods were both significantly depolarized. We also found evidence for altered calcium homeostasis and increased activation of the protease calpain in Cngb1/Hcn1 double-KO mice. Finally, the deletion of HCN1 also exacerbated degeneration of cone photoreceptors in a mouse model of CNGA3-linked achromatopsia. Our results identify HCN1 as a major modifier of photoreceptor degeneration and suggest that pharmacological inhibition of HCN channels may enhance disease progression in RP and achromatopsia patients.
authors.affiliation: Center for Integrated Protein Science Munich CiPSM at the Department of Pharmacy - Center for Drug Research.
authors.forename: Christian
authors.initials: C
authors.lastname: Schön
authors.affiliation: Department of Translational Research, University of Pisa, Pisa, Italy and.
authors.forename: Sabrina
authors.initials: S
authors.lastname: Asteriti
authors.affiliation: Center for Integrated Protein Science Munich CiPSM at the Department of Pharmacy - Center for Drug Research.
authors.forename: Susanne
authors.initials: S
authors.lastname: Koch
authors.affiliation: Division of Ocular Neurodegeneration, Institute for Ophthalmic Research, Centre for Ophthalmology, University of Tübingen, Schleichstr. 4/3, 72076 Tübingen, Germany.
authors.forename: Vithiyanjali
authors.initials: V
authors.lastname: Sothilingam
authors.affiliation: Division of Ocular Neurodegeneration, Institute for Ophthalmic Research, Centre for Ophthalmology, University of Tübingen, Schleichstr. 4/3, 72076 Tübingen, Germany.
authors.forename: Marina
authors.initials: M
authors.lastname: Garcia Garrido
authors.affiliation: Division of Ocular Neurodegeneration, Institute for Ophthalmic Research, Centre for Ophthalmology, University of Tübingen, Schleichstr. 4/3, 72076 Tübingen, Germany.
authors.forename: Naoyuki
authors.initials: N
authors.lastname: Tanimoto
authors.affiliation: German Center for Neurodegenerative Diseases (DZNE), Center for Neuropathology and Prion Research (ZNP) and Munich Cluster of Systems Neurology (SyNergy), Ludwig-Maximilians-Universität München, Munich, Germany.
authors.forename: Jochen
authors.initials: J
authors.lastname: Herms
authors.affiliation: Division of Ocular Neurodegeneration, Institute for Ophthalmic Research, Centre for Ophthalmology, University of Tübingen, Schleichstr. 4/3, 72076 Tübingen, Germany.
authors.forename: Mathias W
authors.initials: MW
authors.lastname: Seeliger
authors.affiliation: Department of Translational Research, University of Pisa, Pisa, Italy and.
authors.forename: Lorenzo
authors.initials: L
authors.lastname: Cangiano
authors.affiliation: Center for Integrated Protein Science Munich CiPSM at the Department of Pharmacy - Center for Drug Research.
authors.forename: Martin
authors.initials: M
authors.lastname: Biel
authors.affiliation: Center for Integrated Protein Science Munich CiPSM at the Department of Pharmacy - Center for Drug Research, michalakis@lmu.de.
authors.forename: Stylianos
authors.initials: S
authors.lastname: Michalakis
mesh_terms: D000818:Animals; D003117:Color Vision Defects / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D054815:Cyclic Nucleotide-Gated Cation Channels / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D018450:Disease Progression; D064428:Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels / Q000235:genetics* / Q000378:metabolism*; D008564:Membrane Potentials / Q000502:physiology; D051379:Mice; D018345:Mice, Knockout; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism; D015221:Potassium Channels / Q000235:genetics* / Q000378:metabolism*; D012160:Retina / Q000378:metabolism / Q000473:pathology; D017949:Retinal Cone Photoreceptor Cells / Q000378:metabolism; D012162:Retinal Degeneration / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D017948:Retinal Rod Photoreceptor Cells / Q000378:metabolism; D012174:Retinitis Pigmentosa / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D014785:Vision, Ocular
chemical_list: C518237:Cnga3 protein, mouse; C529481:Cngb1 protein, mouse; D054815:Cyclic Nucleotide-Gated Cation Channels; C578666:Hcn1 protein, mouse; D064428:Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels; D009419:Nerve Tissue Proteins; D015221:Potassium Channels