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Nobel Prize Awarded for Fundamental Discoveries About G-protein-Coupled Receptors and Cellular Signaling

By BiotechDaily International staff writers
Posted on 16 Oct 2012
Image: 2012 Chemistry Nobel laureate Prof. Robert J. Lefkowitz (Photo courtesy of the American Society for Pharmacology and Experimental Therapeutics).
Image: 2012 Chemistry Nobel laureate Prof. Robert J. Lefkowitz (Photo courtesy of the American Society for Pharmacology and Experimental Therapeutics).
Image: 2012 Chemistry Nobel laureate Prof. Brian K. Kobilka (Photo courtesy of the Nobel Foundation).
Image: 2012 Chemistry Nobel laureate Prof. Brian K. Kobilka (Photo courtesy of the Nobel Foundation).
The 2012 Nobel Prize for Chemistry jointly awarded to scientists Robert J. Lefkowitz and Brian K. Kobilka recognizes the discovery of G-protein-coupled receptors (GPCRs) and fundamental discoveries about their molecular structure, functional roles, and signaling mechanisms. The prize also reflects recognition that much progress made in medical therapy has been specifically based on knowledge about this large family of signaling receptors.

Until the mid-20th century, scientists only knew that certain molecules, such as hormones, in some way enabled cells to sense certain environmental conditions and initiate powerful biological effects. It was suspected that cell surfaces contained some kind of receptors for these extracellular molecules, but what they consisted of and how they functioned remained obscure. Prof. Lefkowitz, currently a Howard Hughes Medical Institute (Chevy Chase, MD, USA) investigator and professor at Duke University Medical Center (Durham, NC, USA), began by using radioactive, iodine isotope labeled hormones to trace cell surface receptors. By 1968, his team unveiled several receptors, among them the β-adrenergic receptor for adrenalin, which the team extracted from the cell membrane and gained an initial understanding of how it works.

The team achieved its next big step during the 1980s. The newly recruited Brian Kobilka, now professor at Stanford University School of Medicine (Stanford, CA, USA), accepted and, with a creative approach, succeeded in the challenge to isolate from the human genome and sequence the gene for the β-adrenergic receptor. They and other researchers eventually discovered that there is a large family of similar receptors, commonly referred to as the GPCR related family (less commonly, the 7TM [7 transmembrane] receptor family). Over a thousand known genes presently make up this family and include receptors for light, taste, odor, adrenalin, histamine, dopamine, and serotonin. In addition to regulation by ligand molecules, other researchers have found a few GPCRs that are also highly regulated by voltage change signals, such as the voltage-dependent regulation of at least two GPCRs involved in the fast-kinetics form of neurotransmitter release, the M2-muscarinic receptor (M2R) in acetylcholine release and the glutamatergic receptor (e.g., mGluR3) in glutamate release. More recently, by 2011, the research team led by Prof. Kobilka achieved another challenging breakthrough – they captured a structural image of the β-adrenergic receptor at the moment of hormone activation.

Prof. Lefkowitz’s laboratory also discovered two families of proteins that desensitize GPCRs, the GPCR kinases (GRKs) and the arrestins; a finding that has helped scientists understand how receptors become tolerant to certain drugs. About doing research, Prof. Lefkowitz says it "continuously renews itself and always feels fresh. I come to work every day with a sense of great anticipation and curiosity about what new discoveries and insights will come our way." The studies by Prof. Lefkowitz and Prof. Kobilka have turned out to be crucial for understanding how GPCRs function as well as for advancement of medical therapy - many important pharmaceutical drugs achieve their effects through GPCRs due to the critical roles of these receptors in almost all physiological processes.

Related Links:

Duke University Medical Center
Howard Hughes Medical Institute
Stanford University School of Medicine



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