The role of cGMP-signalling and calcium-signalling in photoreceptor cell death: perspectives for therapy development

Abstract

The second messengers, cGMP and Ca²⁺, have both been implicated in retinal degeneration; however, it is still unclear which of the two is most relevant for photoreceptor cell death. This problem is exacerbated by the close connections and crosstalk between cGMP-signalling and calcium (Ca²⁺)-signalling in photoreceptors. In this review, we summarize key aspects of cGMP-signalling and Ca²⁺-signalling relevant for hereditary photoreceptor degeneration. The topics covered include cGMP-signalling targets, the role of Ca²⁺ permeable channels, relation to energy metabolism, calpain-type proteases, and how the related metabolic processes may trigger and execute photoreceptor cell death. A focus is then put on cGMP-dependent mechanisms and how exceedingly high photoreceptor cGMP levels set in motion cascades of Ca²⁺-dependent and independent processes that eventually bring about photoreceptor cell death. Finally, an outlook is given into mutation-independent therapeutic approaches that exploit specific features of cGMP-signalling. Such approaches might be combined with suitable drug delivery systems for translation into clinical applications.

Keywords: CNG channel; Ca2+; PKG; Photoreceptor degeneration; Protein kinase G; Retina; cGMP.

Fig. 1

Interplay of cGMP and Ca²⁺ in photoreceptor outer segments. In darkness, Ca²⁺ prevents guanylyl cyclase–activating protein (GCAP) from activating retinal guanylyl cyclase (GC). GC produces cGMP, which opens the cyclic nucleotide–gated channel (CNGC), allowing for influx of Ca²⁺. In light, phototransduction leads to activation of phosphodiesterase-6 (PDE6), which hydrolyses cGMP, closing CNGC and stopping Ca²⁺ influx. This in turn leads to disinhibition of cGMP synthesis. Mutations in genes encoding for any of these proteins lead to dysregulation of cGMP and Ca²⁺ homoeostasis and can cause retinal degeneration (RD)

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