In the first segment of the lecture, the history of discovery in the field of seven transmembrane receptor research over the past forty years is reviewed. Highlights include overcoming initial skepticism that the receptors even existed; isolating the receptors as discrete biochemical entities and demonstrating their ligand binding and functional activating properties; discovering their seven transmembrane spanning arrangement and homology with the visual light receptor rhodopsin, thereby leading to the discovery of the wider seven transmembrane receptor superfamily; determination of the structure – function relationships of the receptors by mutagenesis and chimeric receptor construction; discovery of constitutively active mutant receptors; discovery of the phosphorylation of the receptors by G protein coupled receptor kinases, and of the ?-arrestins and of their universal mechanism for desensitizing the receptors.
In part 2 of the lecture, recent discoveries about how ?-arrestins not only desensitize the receptors but also mediate their endocytosis, as well as independent signaling pathways, are reviewed. Also covered is how these new discoveries provide a basis for designing novel classes of pharmacological agents which can promote signaling exclusively down either the G protein or ?-arrestin mediated pathways, so called “biased” agonists.
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