Fig. 9

Experimental interventions and their relation to Ca²⁺ signalling in cGMP-dependent rd1 degeneration. In rd1 photoreceptors, the Pde6b mutation induces cGMP accumulation, which activates cyclic-nucleotide-gated channels (CNGC), leading to Na⁺ and Ca²⁺ influx. CNGC-dependent depolarization activates voltage-gated Ca²⁺ channel (VGCC) and may reverse directionality of Na⁺/Ca²⁺ exchanger (NCX), both leading to more Ca²⁺-influx. Additional Ca²⁺-influx may be mediated by Ca²⁺ release activated channel (CRAC). All these Ca²⁺ permeable channels may contribute to intracellular Ca²⁺ overload, which, in turn, may activate calpain-2 directly and poly(ADP-ribose)-polymerase (PARP) indirectly. On the one hand, over-activated calpain-2 increases proteolysis of neuroprotective calpain-1. On the other hand, Ca²⁺-dependent activation of PARP may positively feedback on Ca²⁺-influx via NAD⁺ depletion, which may reduce the protective activity of NAD⁺-dependent sirtuins. Eventually, the activities of calpain-2 and PARP, triggered by high intracellular Ca²⁺-levels promote photoreceptor cell death. The drugs used in this study and their targets are indicated. Red colour indicates destructive processes and drugs, while green labelled proteins and compounds promote photoreceptor survival, grey indicates absence of a clear beneficial or destructive effect