gms | German Medical Science

Phototransduction begins with the activation of visual pigments, which subsequently activate phosphodiesterase 6 (PDE6). This results in cGMP degradation, leading to the initiation of electrical current flow across the retina. Similarly, the visual cycle begins with the activation of visual pigments that are covalently bonded to 11-cis-retinal. Upon exposure to light, the chromophore isomerizes to all-trans-retinal, which is then released from the activated opsin.

Given their vital roles in transmitting signals from photon arrival to electrical signals processed by the brain, protein dysfunctions in the phototransduction and visual cycle often lead to several diseases. However, these proteins also have the potential to be excellent biomarkers for evaluating retinal function and tracking treatment efficacy. Two applications in this field are two-photon imaging and optoretinography (ORG). While two-photon imaging can track natural fluorescent retinoid molecules and detect imbalances in the visual cycle, ORG enables the detection of nanometer-scale changes in photoreceptors upon light stimulus within milliseconds. However, the data’s utility remains limited without identifying the molecular drivers behind these measurable or quantifiable change.

In our studies, we harness structural biology methods to gain insights into and identify the molecular drivers of biomarkers detected by functional imaging systems or to develop direct measurements of their in-situ performance. In particular, we have improved the resolution of the retinol-binding protein 3 (RBP3) cryoEM structure and analyzed its conformational changes in solution, offering potential use in diabetic retinopathy diagnosis by direct quantification of RBP3 using two-photon imaging. Furthermore, we have obtained cryoEM tomograms of rod outer segments (ROS) in an attempt to identify PDE6 as the molecular driver of the photoreceptors’ morphological changes upon light stimulus that underpins the ORG system. Photopic flicker ORG (f-ORG) enables noninvasive, high-resolution tracking of retinal photoreceptor function by capturing nanometric, light-induced morphological changes. This method holds high translational potential as a functional biomarker for early disease detection, treatment monitoring, and therapeutic response assessment — without requiring dark adaptation or contact-based setup. For clinicians, f-ORG may represent a new frontier in rapid, patient-friendly diagnostics, bridging molecular processes with real-time functional imaging.