Fig. 2.

cGMP and Ca²⁺ signalling in different photoreceptor compartments. In RD-type diseases, photoreceptor degeneration was connected to high levels of cGMP and Ca²⁺. cGMP activates protein kinase G (PKG), which is linked to cell death, and cyclic nucleotide–gated ion channel (CNGC), promoting Ca²⁺ influx in the outer segment. In turn, Ca²⁺ can inhibit guanylate cyclase (GC), which converts GTP to cGMP. The cGMP signal is normally terminated by phosphodiesterase 6 (PDE6). Several channels are responsible for Ca²⁺ homeostasis: The Na⁺/Ca²⁺/K⁺ exchanger (NCKX) promotes Ca²⁺ efflux for Na⁺ influx. Excess Na⁺ is then expelled by the ATP-driven Na⁺/K⁺ exchanger (NKX) in the inner segment. Plasma membrane Ca²⁺ ATPase (PMCA) also extrudes Ca²⁺ in exchange for ATP hydrolysis. In the synapse and cell body, voltage-gated calcium channel (VGCC) is responsible for Ca²⁺ influx, which may activate calpain-type proteases to precipitate cell death. In the synapse, Ca²⁺ stimulates glutamate-containing vesicles to fuse with the membrane, regulating glutamate release