Newly discovered structure of the protein receptor that controls our response to stress
Scientists working to design advanced medicines that are perfectly targeted to control the body’s natural receptors have made a major discovery using Diamond’s Microfocus Macromolecular Crystallography beamline (I24). For the first time, they have been able to visualise and study the structure of CRF1, the protein receptor in the brain which controls our response to stress.
Heptares Therapeutics, a leading UK-based drug discovery and development company, was responsible for identifying the 3D structure of the ‘stress’ receptor, and their results are published today in the journal Nature. This discovery will help scientists to develop improved treatments for depression and anxiety. Furthermore, having identified the architecture of CRF1, scientists now have a template that can be used to accelerate research into other protein receptors that are known to be in the same ‘family’, including those that can be targeted to treat Type 2 diabetes and osteoporosis.
Stress-related diseases such as depression and anxiety are now commonplace. 1 in 4 people experience some kind of mental health problem in the course of a year. Over 105 million work days are lost to stress each year, costing UK employers £1.2 billion.
The UK also faces a major health challenge from diabetes. In the past 20 years, the number of people in the country suffering from diabetes has more than doubled to 2.9 million. By 2025 it is estimated that 5 million people will have diabetes, and that most of these cases will be Type 2 diabetes.
Heptares is a leader in the development of drugs targeting certain protein receptors, called G protein-coupled receptors. Currently 30% of drugs for a variety of diseases target these receptors, making them the largest and most important family of drug targets in the human body.
In the past, drug design has been largely the product of trial and error. Drugs would be developed and then tested until they had the desired effect. Because scientists lacked a comprehensive understanding of why and how the drugs were working, this approach could lead to unwanted side-effects.
A new way of making medicines, known as rational drug design, produces drugs that are specifically targeted to protein receptors in the body. By visualising the stress protein receptor at the atomic level, they were able, for the first time, to identify a ‘pocket’ in the structure. Computer technology will allow scientists to design a drug to fit precisely into this pocket, inhibiting the response of the ‘stress’ receptor. Such focused targeting will only affect the receptor they are aiming for and reduce the chance of unexpected side effects. The level of detail required for this work could only be achieved using the intense synchrotron light produced at Diamond Light Source, the UK’s synchrotron science facility in Oxfordshire. The synchrotron speeds electrons to near light speed, producing a light 10 billion times brighter than the sun. Around 2,500 scientists a year use this light to study samples, and its intensity allows them to visualise on a scale that is unobtainable in their home laboratories. Heptares is currently the biggest annual industrial user of the synchrotron.
Why do females respond better to stress? New study suggests it’s because of estrogen in the brain ?
he idea that females are more resilient than males in responding to stress is a popular view, and now University at Buffalo researchers have found a scientific explanation. The paper describing their embargoed study will be published July 9 online, in the high-impact journal, Molecular Psychiatry.
“We have examined the molecular mechanism underlying gender-specific effects of stress,” says senior author Zhen Yan, PhD, a professor in the Department of Physiology and Biophysics in the UB School of Medicine and Biomedical Sciences. “Previous studies have found that females are more resilient to chronic stress, and now our research has found the reason why.”
The research shows that in rats exposed to repeated episodes of stress, females respond better than males because of the protective effect of estrogen. In the UB study, young female rats exposed to one week of periodic physical restraint stress showed no impairment in their ability to remember and recognize objects they had previously been shown. In contrast, young males exposed to the same stress were impaired in their short-term memory.
An impairment in the ability to correctly remember a familiar object signifies some disturbance in the signaling ability of the glutamate receptor in the prefrontal cortex, the brain region that controls working memory, attention, decision-making, emotion and other high-level “executive” processes. Last year, Yan and UB colleagues published in Neuron a paper showing that repeated stress results in loss of the glutamate receptor in the prefrontal cortex of young males. The current paper shows that the glutamate receptor in the prefrontal cortex of stressed females is intact. The findings provide more support for a growing body of research demonstrating that the glutamate receptor is the molecular target of stress, which mediates the stress response.
The stressors used in the experiments mimic challenging and stressful, but not dangerous, experiences that humans face, such as those causing frustration and feelings of being under pressure, Yan says. By manipulating the amount of estrogen produced in the brain, the UB researchers were able to make the males respond to stress more like females and the females respond more like males.
“When estrogen signaling in the brains of females was blocked, stress exhibited detrimental effects on them,” explains Yan. “When estrogen signaling was activated in males, the detrimental effects of stress were blocked. “We still found the protective effect of estrogen in female rats whose ovaries were removed,” says Yan. “It suggests that it might be estrogen produced in the brain that protects against the detrimental effects of stress.”
In the current study, Yan and her colleagues found that the enzyme aromatase, which produces estradiol, an estrogen hormone, in the brain, is responsible for female stress resilience. They found that aromatase levels are significantly higher in the prefrontal cortex of female rats. “If we could find compounds similar to estrogen that could be administered without causing hormonal side effects, they could prove to be a very effective treatment for stress-related problems in males,” she says. She notes that while stress itself is not a psychiatric disorder, it can be a trigger for the development of psychiatric disorders in vulnerable individuals.