Systems Pharmacology Links GPCRs with Retinal Degenerative Disorders

Abstract

In most biological systems, second messengers and their key regulatory and effector proteins form links between multiple cellular signaling pathways. Such signaling nodes can integrate the deleterious effects of genetic aberrations, environmental stressors, or both in complex diseases, leading to cell death by various mechanisms. Here we present a systems (network) pharmacology approach that, together with transcriptomics analyses, was used to identify different G protein–coupled receptors that experimentally protected against cellular stress and death caused by linked signaling mechanisms. We describe the application of this concept to degenerative and diabetic retinopathies in appropriate mouse models as an example. Systems pharmacology also provides an attractive framework for devising strategies to combat complex diseases by using (repurposing) US Food and Drug Administration–approved pharmacological agents.

Transcriptome profiling of NIH3T3 cell lines expressing opsin and the P23H opsin mutant identifies candidate drugs for the treatment of retinitis pigmentosa

“…Thus, the initial specificity of a drug does not guarantee its long-term effectiveness or safety. Rather, genetic profiling can assess the molecular consequences in multiple cell-types associated with a particular drug treatment and thereby improve ultimate drug design [73]. …”

Hydrogen/Deuterium Exchange Mass Spectrometry of Human Green Opsin Reveals a Conserved Pro-Pro Motif in Extracellular Loop 2 of Monostable Visual G Protein-Coupled Receptors

“…12–14 Different oligomeric organizations may affect signaling and other physiological properties of these receptors and can, therefore, serve as distinct targets for drug screens. 15,16 Opsins are known to form homodimers and higher oligomeric structures, as shown by cryo-electron microscopy, atomic force microscopy, and fluorescence assays. 12,14,17 Disruption of the oligomeric organization of bovine rhodopsin with synthetic peptides confirmed that the dimer interface is located between TM4 and TM5.…”

Next generation sequencing technology and genomewide data analysis: Perspectives for retinal research

“…WES and targeted sequencing are becoming standard methodology for identifying genetic variants/mutations in retinal research and clinical diagnosis. NGS-based methods are increasingly being used to evaluate drug targets and small molecules and their broader impact on retinal cell/tissue function (Chen and Palczewski, 2015; Kaewkhaw, 2016). Over 240 genes have so far been associated with retinal diseases; however, underlying pathways leading to disease pathology are poorly understood.…”