Figure 7.

Differential effects of experimental conditions on cGMP-dependent cell death in rd1 photoreceptors. The mutation-induced cGMP accumulation activates cyclic nucleotide-gated (CNG) channels in the outer segment, leading to Na⁺-and Ca²⁺-influx and photoreceptor depolarization. This leads to opening of voltage-gated Ca²⁺-channels (VGCCs) in the cell body, causing further Ca²⁺- influx. In the cell body, high Ca²⁺ levels may activate calpain if not controlled by ATP-dependent plasma membrane Ca²⁺-ATPase (PMCA). In addition, cGMP-dependent activation of protein kinase G (PKG) has been associated with histone-deacetylase (HDAC) activity, causing chromatin condensation and DNA breaks, which may trigger PARP activation. Excessive consumption of NAD⁺ by PARP and the production of PAR may cause mitochondrial dysfunction, leading to ATP shortage. Calpastatin treatment blocks calpain activation, decreasing proteolytic damage to the cell, even in the presence of CNG channel/VGCC-mediated Ca²⁺-influx. D-cis-diltiazem inhibits VGCCs in the cell body, reducing intracellular Ca²⁺-levels and calpain activity. Moreover, VGCCs could be involved in PARP activation, even though D-cis-diltiazem fails to delay rd1 rod degeneration. Olaparib blocks PARP activity, decreasing NAD⁺ consumption and PAR generation. This may preserve mitochondrial function and intracellular ATP levels, allowing PMCA to extrude Ca²⁺ and keeping calpain activity low.