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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 Ca 2+ —signaling. Ca 2+  can enter the photoreceptor cell via outer segment cyclic nucleotide-gated (CNG) channels or synaptic Ca v 1.4 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 Ca v 1.4 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 Ca 2+ -dependent protease calpain during photoreceptor loss. Our results show that genetic deletion of the synaptic Ca v 1.4 L-type VGCCs impairs calpain activation and leads to a short-term preservation of photoreceptors in the  rd1  mouse.

Cav1.4 L-Type Calcium Channels Contribute to Calpain Activation in Degenerating Photoreceptors of rd1 Mice