Biology, Pathobiology and Gene Therapy of CNG Channel-Related Retinopathies

Maximilian J Gerhardt; Siegfried G Priglinger; Martin Biel; Stylianos Michalakis

doi:10.3390/biomedicines11020269

Biology, Pathobiology and Gene Therapy of CNG Channel-Related Retinopathies

Biomedicines. 2023 Jan 19;11(2):269. doi: 10.3390/biomedicines11020269.

Authors

Maximilian J Gerhardt¹, Siegfried G Priglinger¹, Martin Biel², Stylianos Michalakis¹

Affiliations

¹ Department of Ophthalmology, University Hospital, LMU Munich, Mathildenstraße 8, 80336 Munich, Germany.
² Department of Pharmacy-Center for Drug Research, Ludwig-Maximilians-Universität München, 81377 Munich, Germany.

Abstract

The visual process begins with the absorption of photons by photopigments of cone and rod photoreceptors in the retina. In this process, the signal is first amplified by a cyclic guanosine monophosphate (cGMP)-based signaling cascade and then converted into an electrical signal by cyclic nucleotide-gated (CNG) channels. CNG channels are purely ligand-gated channels whose activity can be controlled by cGMP, which induces a depolarizing Na⁺/Ca²⁺ current upon binding to the channel. Structurally, CNG channels belong to the superfamily of pore-loop cation channels and share structural similarities with hyperpolarization-activated cyclic nucleotide (HCN) and voltage-gated potassium (KCN) channels. Cone and rod photoreceptors express distinct CNG channels encoded by homologous genes. Mutations in the genes encoding the rod CNG channel (CNGA1 and CNGB1) result in retinitis-pigmentosa-type blindness. Mutations in the genes encoding the cone CNG channel (CNGA3 and CNGB3) lead to achromatopsia. Here, we review the molecular properties of CNG channels and describe their physiological and pathophysiological roles in the retina. Moreover, we summarize recent activities in the field of gene therapy aimed at developing the first gene therapies for CNG channelopathies.

Keywords: CNG; Ca2+; IRD; RP; achromatopsia; cGMP; channelopathies; cyclic nucleotide-gated channel; gene therapy; inherited retinal disease; knockout; photoreceptor; retinitis pigmentosa; vision.

Publication types

Review

Grants and funding

This work was supported by the Deutsche Forschungsgemeinschaft (DFG). The funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript; or in the decision to publish the results.