Cav1.4 L-Type Calcium Channels Contribute to Calpain Activation in Degenerating Photoreceptors of rd1 Mice.
Retinitis pigmentosa is an inherited blinding disorder characterized by progressive degeneration and loss of photoreceptors. The exact mechanism of degeneration and cell death of photoreceptors is not known, but is thought to involve disturbed Ca2+-signaling. Ca2+ can enter the photoreceptor cell via outer segment cyclic nucleotide-gated (CNG) channels or synaptic Cav1.4 L-type voltage-gated calcium channels (VGCC). Previously, we have shown that genetic ablation of the Cngb1 gene encoding the B subunit of the rod CNG channel delays the fast progressing degeneration in the rd1 mutant mouse model of retinitis pigmentosa. In this study, we crossbred rd1 mice with the Cacna1f-deficient mouse lacking the Cav1.4 α1 subunit of the L-type VGCC. Longitudinal in vivo examinations of photoreceptor layer thickness by optical coherence tomography revealed a significant, but not sustained delay of retinal degeneration in Cacna1f x rd1 double mutant mice compared to rd1 mice. This was accompanied by a reduction of TUNEL positive cells in the early phase of rod degeneration. Remarkably, Cacna1f x rd1 double mutant mice displayed a strong decrease in the activation of the Ca2+-dependent protease calpain during photoreceptor loss. Our results show that genetic deletion of the synaptic Cav1.4 L-type VGCCs impairs calpain activation and leads to a short-term preservation of photoreceptors in the rd1 mouse.
Center for Integrated Protein Science Munich CiPSM at the Department of Pharmacy - Center for Drug Research, Ludwig-Maximilians-Universität München, Munich, Germany.
Christian
C
Schön
Division of Ocular Neurodegeneration, Institute for Ophthalmic Research, Centre for Ophthalmology, University of Tübingen, Schleichstr. 4/3, 72076, Tübingen, Germany.
François
F
Paquet-Durand
Center for Integrated Protein Science Munich CiPSM at the Department of Pharmacy - Center for Drug Research, Ludwig-Maximilians-Universität München, Munich, Germany.
Stylianos
S
Michalakis
D000818:Animals; D002118:Calcium / Q000378:metabolism; D015220:Calcium Channels / Q000172:deficiency* / Q000235:genetics; D020746:Calcium Channels, L-Type; D002154:Calpain / Q000378:metabolism*; D054707:Cyclic Nucleotide Phosphodiesterases, Type 6 / Q000235:genetics*; D004195:Disease Models, Animal; D051379:Mice; D018345:Mice, Knockout; D009154:Mutation; D012162:Retinal Degeneration; D017948:Retinal Rod Photoreceptor Cells / Q000166:cytology / Q000378:metabolism / Q000473:pathology*; D012174:Retinitis Pigmentosa / Q000000981:diagnostic imaging / Q000235:genetics* / Q000473:pathology; D041623:Tomography, Optical Coherence / Q000379:methods
C480684:Cacna1f protein, mouse; D015220:Calcium Channels; D020746:Calcium Channels, L-Type; D054707:Cyclic Nucleotide Phosphodiesterases, Type 6; C517438:Pde6b protein, mouse; D002154:Calpain; D002118:Calcium