The influence of native lipids on rhodopsin action and generation may usher in a new paradigm for discovery of drugs that target G protein-coupled receptors (GPCRs), reveal researchers at the University of California.
Functionally, GPCRs are cell surface receptors that respond to a number of stimuli to activate indicating pathways across cell membranes. In terms of structure, GPCRs are membrane bound and have rarely been understood in their native membrane environments.
Meanwhile, recent studies for GPCRs have produced atomic structures of key intermediates and roles of lipids in mediating the signalling. However, so far, real-time capture of signalling events of a wild-type receptor across an indigenous membrane to its downstream effectors has remained difficult.
Importantly, the receptors represent the largest class of drug targets, and a vast number of approved drugs control their function.
The findings of the study is published in Nature.
To develop the drug target, researchers used mass spectrometry to probe the archetype class A GPCR for directly in fragments of native disk membranes. This involved real-time monitorinf of photoconversion of dark-adapted rhodopsin to opsin, thereby delineating the stage wise isomerization of retinal and hydrolysis of the retinal-opsin adduct. This leads to further discovery that the reaction is significantly slower in its natural membrane environment than in artificial environments.
In fact, the function of GPCRs highly impacts human diseases ranging from cardiovascular diseases to cancer and blindness. Besides quantitative analysis of the signalling function, the novel technology has enabled direct identification of new potential targets of therapeutic significance for the visual system, within the native membranes.
The ejection of lipids along with rhodopsin from the membrane pieces in the mass spectrometer enabled researchers to demonstrate that opsin can be regenerated in the membranes.