Feedback

cGMP Analogues with Opposing Actions on CNG Channels Selectively Modulate Rod or Cone Photoreceptor Function

Affiliation
Institute of Physiology II, University Hospital Jena, Friedrich Schiller University Jena, 07743 Jena, Germany
Wucherpfennig, Sophie;
ORCID
0000-0003-0890-9780
Affiliation
Neuroretinal Electrophysiology and Imaging, Institute for Ophthalmic Research, University of Tübingen, 72076 Tübingen, Germany
Haq, Wadood;
Affiliation
Institute of Physiology II, University Hospital Jena, Friedrich Schiller University Jena, 07743 Jena, Germany
Popp, Valerie;
ORCID
0000-0003-0368-9846
Affiliation
Institute of Physiology II, University Hospital Jena, Friedrich Schiller University Jena, 07743 Jena, Germany
Kesh, Sandeep;
ORCID
0000-0002-2067-960X
Affiliation
Cell Death Mechanism Group, Institute for Ophthalmic Research, University of Tübingen, 72076 Tübingen, Germany
Das, Soumyaparna;
ORCID
0000-0002-1870-9419
Affiliation
Biomolecular Photonics Group, University Hospital Jena, Friedrich Schiller University Jena, 07743 Jena, Germany
Melle, Christian;
ORCID
0000-0003-4792-131X
Affiliation
Biolog Life Science Institute GmbH & Co. KG, 28199 Bremen, Germany
Rentsch, Andreas;
Affiliation
Biolog Life Science Institute GmbH & Co. KG, 28199 Bremen, Germany
Schwede, Frank;
ORCID
0000-0001-7355-5742
Affiliation
Cell Death Mechanism Group, Institute for Ophthalmic Research, University of Tübingen, 72076 Tübingen, Germany
Paquet-Durand, François;
ORCID
0000-0003-0884-2651
Affiliation
Institute of Physiology II, University Hospital Jena, Friedrich Schiller University Jena, 07743 Jena, Germany
Nache, Vasilica

The vertebrate retina harbors rod and cone photoreceptors. Human vision critically depends on cone photoreceptor function. In the phototransduction cascade, cGMP activates distinct rod and cone isoforms of the cyclic nucleotide-gated (CNG) channel. Excessive cGMP levels initiate a pathophysiological rollercoaster, which starts with CNG channel over-activation, typically in rod photoreceptors. This triggers cell death of rods first, and then cones, and is the root cause of many blinding retinal diseases, including Retinitis pigmentosa . While targeting of CNG channels has been proposed for therapeutic purposes, thus far, it has not been possible to inhibit rod CNG channels without compromising cone function. Here, we present a novel strategy, based on cGMP analogues with opposing actions on CNG channels, which enables the selective modulation of either rod or cone photoreceptor activity. The combined treatment with the weak rod-selective CNG-channel inhibitor (Rp-8-Br-PET-cGMPS) and the cone-selective CNG-channel activator (8-pCPT-cGMP) essentially normalized rod CNG-channel function while preserving cone functionality at physiological and pathological cGMP levels. Hence, combinations of cGMP analogues with desired properties may elegantly address the isoform-specificity problem in future pharmacological therapies. Moreover, this strategy may allow for improvements in visual performance in certain light environments.

Cite

Citation style:
Could not load citation form.

Rights

License Holder: © 2022 by the authors.

Use and reproduction: