Abstract
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.
Highlights
Retinitis pigmentosa (RP) is characterized by a primary loss of rod photoreceptor function and structure
Two different types of ion channels are known to mediate Ca2+— influx into photoreceptors: the cyclic nucleotide-gated (CNG) channel found in the outer segment plasma membrane [5] and the synaptic L-type voltage-gated Ca2+ channel (VGCC) [6, 7]
Given the importance of Ca2+—influx for photoreceptor degeneration [8], the Ca2+-conducting CNG channels and VGCCs were proposed as potential therapeutic targets for RP [4, 9]
Summary
Retinitis pigmentosa (RP) is characterized by a primary loss of rod photoreceptor function and structure. The most extensively studied RP model is the rd mutant mouse [1]—a naturally occurring strain expressing a loss-of-function mutation in the Pde6b gene encoding the β-subunit of the rod-specific cGMP phosphodiesterase 6 [2]. This mutation results in a fast progressive. Genetic studies helped clarifying this discrepancy and showed that the knockout of the Cngb gene encoding for the β1-subunit of the rod CNG channel significantly delayed photoreceptor degeneration in rd1mt/mt mice [14, 15]. Genetic deletion of Cacnb encoding the β2-subunit of the VGCC resulted in a significant, but only transient decrease in the rate of photoreceptor degeneration in rd1mt/mt mice (15)
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