Genetic Engineering & Biotechnology News

JUN15 2018

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Page 14 of 37 | Genetic Engineering & Biotechnology News | JUNE 15, 2018 | 13 through. Drugs targeting the APJ pathway are "potentially valuable in treating cardio- vascular disease," he explains, because they address both problems at the same time. This is a new target and apelin drugs have not yet entered the clinic. Unfortunately, many of the drugs target- ing the family of receptors that include apelin don't just produce the beneficial effects of acti- vating the G-protein signaling pathway inside the cell. They also activate a second group of intercellular proteins, called beta-arrestins, which reduce the sensitivity of APJ to further signaling and mean higher doses of the drug are needed to generate the same effect. Dr. Davenport and his team have found a small molecule, potentially suitable as an oral once-a-day drug that selectively acti- vates APJ without activating the beta-arres- tin pathway. "What we've shown, for the first time, is that we can produce the benefit of increasing cardiac output, but without desensitizing the receptor," he says. Dr. Dav- enport hopes this will provide an avenue for the development of new drugs. Understanding Overdose "Our overall topic is trying to understand why people die from heroin overdose when they haven't taken much," says Graeme Henderson, Ph.D., professor of pharmacol- ogy at the University of Bristol, U.K. His talk at the 7th Focused Meeting on Cell Signal- ling also covered how GPCRs can be desen- sitized to drugs—in this case, to morphine and methadone. "Our basic premise is that when you take heroin regularly you become tolerant to it, and the tolerance mechanisms involve switching off the opioid receptors by enzymes or kinas- es," says Dr. Henderson. He explains that the kinase that switches off the receptor is differ- ent for morphine and methadone so, although an addict can become tolerant to both, the cell signaling mechanism is different. For morphine, the enzyme involved is protein kinase C (PKC) whereas, for metha- done, it's an enzyme family called G-protein- coupled receptor kinase (GRK). What's novel about his research, he explains, is that his team has moved from studying the basic cell signaling mechanisms to understanding, in an animal model, which enzymes are impor- tant in overdose deaths. When animals were chronically treated with methadone or morphine, they experi- enced a greater amount of respiratory de- pression if they were given ethanol or prega- balin, a prescription drug that is also abused. "What we've shown is that ethanol (al- cohol) and pregabalin reverse tolerance to morphine, but not tolerance to methadone," Dr. Henderson says. "The obvious interpre- tation is that ethanol and pregabalin inhibit PKC, but not GRK." Since drug addicts of- ten take many drugs at the same time, "if you have a drink before shooting up, you'll get more effect of the heroin, more respira- tory depression, and then you can die." Dr. Henderson is currently researching how alcohol and pregabalin might operate to inhibit PKC inside the cell. He explains that PKC and GRK sit a little way from the receptor inside the cell, but move to the recep- tor when it's activated by a drug—a process called translocation. Although the team has no definitive evidence, Dr. Henderson believes that alcohol and pregabalin stop the translo- cation process of the enzyme, reducing its ac- tivity at the receptor. Studying Individual Receptors at Work "We don't fully understand how G-pro- tein-coupled receptors decode signals from the outside," says Davide Calebiro, Ph.D., professor of molecular endocrinology at the Institute of Metabolism and Systems Re- search, University of Birmingham, U.K., and Centre of Membrane Proteins and Receptors (COMPARE) at both Birmingham and Not- tingham Universities, U.K. (Figure 3). He explains that, until recently, scientists believed these receptors were simple on-off switches. They now understand these systems are far more complex—for example, with different drugs producing different effects by acting on the same receptor. Understanding these processes, however, remains difficult, he says, because standard microscopy and biochemical techniques don't have the spatial and temporal resolution required to study re- ceptors on the scale at which crucial signaling events take place. Dr. Calebiro's talk was about single-mol- ecule microscopy as a tool for studying indi- vidual signaling proteins as they move and interact on the surface of living cells. "We can now address fundamental questions about how individual receptors work," he says. His team is among the first to use the technique for GPCR studies. "Our recent study (Sungkaworn et al., Nature 2017) was the first where someone could visualize individual receptors and G proteins, which transmit their signals inside cells, as they interact to produce specific ef- fects—this is very new." Crucial improvements in technology making this work feasible include the devel- opment of new ultrasensitive cameras, he ex- plains, with new models able to capture the few photons emitted by a single molecule. "Until recently, only a few labs in the world could do this kind of work. Now, with cur- rent technology, we can look for a longer time, at different types of molecules with dif- ferent colors simultaneously and go for real biological applications," he says. Drug Discovery Developers of the original Pipet-Aid ® Pipetting, Pipetting, Pipetting. ...Our Reputation is Built on Reliability If you're tired of unreliable equipment, visit because DRUMMOND means QUALITY. Go to to see how the superior ergonomic design of the Pipet-Aid ® XL can change the way you think about lab hood pipetting. 500 Parkway, Box 700 • Broomall, PA 19008 • 800.523.7480 Figure 3. Individual receptors (green) and G proteins (magenta) imaged on the surface of a living cell. Modified from Sungkaworn et al. Nature 2017 Oct 26;550(7677):543-547. doi: 10.1038/nature24264 (image and caption provided by Davide Calebiro, Ph.D.). Figure 2. Computer model of the small molecule apelin agonist binding to two key residues in the apelin receptor (green). Read et al. Biochem Pharmacol 2016 116:63-72. doi:10.1016/ j.bcp.2016.07.018. Image and caption supplied by Anthony Davenport, Ph.D.

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