Cyclic guanosine monophosphate-dependent protein kinase and cyclic nucleotide-gated channels (PKG/CNGC)

cGMP-dependent targets in photoreceptors primarily encompass cyclic nucleotide-gated (CNG) channels and cGMP-dependent protein kinase (PKG). These proteins are central to the phototransduction cascade, where cGMP levels are regulated by light to control ion flow and membrane potential (Power et al., 2020). In various hereditary retinal dystrophies, such as Retinitis Pigmentosa, mutations in genes like PDE6 lead to an abnormal and toxic accumulation of cGMP (Paquet-Durand et al., 2007). This elevation results in the chronic over-activation of CNG channels, causing a lethal influx of calcium ions into the photoreceptor cells, while simultaneously hyper-activating PKG, which initiates a specific, non-apoptotic cell death pathway (Arango-Gonzalez et al., 2014). Targeting these cGMP-dependent effectors has emerged as a promising neuroprotective strategy to prevent the loss of rods and cones. Experimental drugs, including cGMP analogues and specific inhibitors like CN03, are designed to block these pathological signaling events to provide a mutation-independent treatment for diverse forms of blindness (Mireca Medicines, 2024).

Other names

cGMP-dependent targetsPhotoreceptor cGMP-signaling pathwayPKG and CNG channelsCyclic nucleotide-gated ion channelscGMP-dependent protein kinase 1 (PRKG1)cGMP-dependent protein kinase 2 (PRKG2)

Inhibition of cGMP-dependent protein kinase (PKG) activity and/or modulation of cyclic nucleotide-gated (CNG) channel conductance to prevent calcium overload and suppress pro-apoptotic signaling pathways.