Posts tagged receptors
Articles and news from the latest research reports.
Research gives unprecedented 3-D view of important brain receptor
Researchers with Oregon Health & Science University’s Vollum Institute have given science a new and unprecedented 3-D view of one of the most important receptors in the brain — a receptor that allows us to learn and remember, and whose dysfunction is involved in a wide range of neurological diseases and conditions, including Alzheimer’s, Parkinson’s, schizophrenia and depression.
The unprecedented view provided by the OHSU research, published online June 22 in the journal Nature, gives scientists new insight into how the receptor — called the NMDA receptor — is structured. And importantly, the new detailed view gives vital clues to developing drugs to combat the neurological diseases and conditions.
"This is the most exciting moment of my career," said Eric Gouaux, a senior scientist at the Vollum Institute and a Howard Hughes Medical Institute investigator. "The NMDA receptor is one of the most essential, and still sometimes mysterious, receptors in our brain. Now, with this work, we can see it in fascinating detail."
Receptors facilitate chemical and electrical signals between neurons in the brain, allowing those neurons to communicate with each other. The NMDA (N-methyl-D-aspartate) receptor is one of the most important brain receptors, as it facilitates neuron communication that is the foundation of memory, learning and thought. Malfunction of the NMDA receptor occurs when it is increasingly or decreasingly active and is associated with a wide range of neurological disorders and diseases. Alzheimer’s disease, Parkinson’s disease, depression, schizophrenia and epilepsy are, in many instances, linked to problems with NMDA activity.
Scientists across the world study the NMDA receptor; some of the most notable discoveries about the receptor during the past three decades have been made by OHSU Vollum scientists.
The NMDA receptor makeup includes receptor “subunits” — all of which have distinct properties and act in distinct ways in the brain, sometimes causing neurological problems. Prior to Gouaux’s study, scientists had only a limited view of how those subtypes were arranged in the NMDA receptor complex and how they interacted to carry out specific functions within the brain and central nervous system.
Gouaux’s team of scientists – Chia-Hsueh Lee, Wei Lu, Jennifer Michel, April Goehring, Juan Du and Xianqiang Song – created a 3-D model of the NMDA receptor through a process called X-ray crystallography. This process throws x-ray beams at crystals of the receptor; a computer calibrates the makeup of the structure based on how those x-ray beams bounce off the crystals. The resulting 3-D model of the receptor, which looks something like a bouquet of flowers, shows where the receptor subunits are located, and gives unprecedented insight into their actions.
"This new detailed view will be invaluable as we try to develop drugs that might work on specific subunits and therefore help fight or cure some of these neurological diseases and conditions," Gouaux said. "Seeing the structure in more detail can unlock some of its secrets — and may help a lot of people."
Receptor may aid spread of Alzheimer’s and Parkinson’s in brain
Scientists at Washington University School of Medicine in St. Louis have found a way that corrupted, disease-causing proteins spread in the brain, potentially contributing to Alzheimer’s disease, Parkinson’s disease and other brain-damaging disorders.
Image: An electron micrograph shows clumps of corrupted tau protein outside a nerve cell. Scientists have identified a receptor that lets these clumps into the cell, where the corruption can spread. Blocking this receptor with drugs may help treat Alzheimer’s, Parkinson’s and other disorders.
The research identifies a specific type of receptor and suggests that blocking it may aid treatment of theses illnesses. The receptors are called heparan sulfate proteoglycans (HSPGs).
“Many of the enzymes that create HSPGs or otherwise help them function are good targets for drug treatments,” said senior author Marc I. Diamond, MD, the David Clayson Professor of Neurology. “We ultimately should be able to hit these enzymes with drugs and potentially disrupt several neurodegenerative conditions.”
The study is available online in the Proceedings of the National Academy of Sciences.
Over the last decade, Diamond has gathered evidence that Alzheimer’s disease and other neurodegenerative diseases spread through the brain in a fashion similar to conditions such as mad cow disease, which are caused by misfolded proteins known as prions.
Proteins are long chains of amino acids that perform many basic biological functions. A protein’s abilities are partially determined by the way it folds into a 3-D shape. Prions are proteins that have become folded in a fashion that makes them harmful.
Prions spread across the brain by causing other copies of the same protein to misfold.
Among the most infamous prion diseases are mad cow disease, which rapidly destroys the brain in cows, and a similar, inherited condition in humans called Creutzfeldt-Jakob disease.
Diamond and his colleagues have shown that a part of nerve cells’ inner structure known as tau protein can misfold into a configuration called an amyloid. These corrupted versions of tau stick to each other in clumps within the cells. Like prions, the clumps spread from one cell to another, seeding further spread by causing copies of tau protein in the new cell to become amyloids.
In the new study, first author Brandon Holmes, an MD/PhD student, showed that HSPGs are essential for binding, internalizing and spreading clumps of tau. When he genetically disabled or chemically modified the HSPGs in cell cultures and in a mouse model, clumps of tau could not enter cells, thus inhibiting the spread of misfolded tau from cell to cell.
Holmes also found that HSPGs are essential for the cell-to-cell spread of corrupted forms of alpha-synuclein, a protein linked to Parkinson’s disease.
“This suggests that it may one day be possible to unify our understanding and treatment of two or more broad classes of neurodegenerative disease,” Diamond said.
“We’re now sorting through about 15 genes to determine which are the most essential for HSPGs’ interaction with tau,” Holmes said. “That will tell us which proteins to target with new drug treatments.”
(Source: news.wustl.edu)
Brain capable of making its own version of Valium
The oral drug Valium – also known by its generic name, diazepam – was once popular with doctors in the 1970s as a treatment for seizures brought on by epilepsy. However, the drug, also used to treat anxiety, has fallen out of favor in recent years as it is prone to abuse and often dangerous if taken in high doses.
Now, in light of a recent study, the need for Valium to treat epilepsy may be even further diminished. Researchers from Stanford University School of Medicine have discovered a naturally occurring protein in the brains of mammals that acts like Valium, stopping certain types of seizures from occurring. Researchers hope that if they are able to discover a way to boost this protein naturally, doctors would no longer have a need to prescribe Valium.
The protein, identified as diazepam binding inhibitor (DBI), essentially acts like the brain’s very own brake system, sensing when a seizure is about to occur and arresting the process before it can spiral out of control.
“Our thinking on brain circuits and epilepsy has been that our brains have their own ways to control seizures, and this is why most of us aren’t having seizures every day,” study author John Huguenard, professor of neurology and neurological sciences at Stanford, told FoxNews.com. “But what happens as a seizure starts, a few cells in the brain may get too active, and you get an avalanche of activity that eventually can take up most of the brain circuitry. The brain’s own ‘Valium’ is acting as an anti-avalanche method, checking things when they’re first starting.”
According to Huguenard, the brain has two main groups of nerve cells. The first type of cells – excitatory cells – are responsible for stimulating other cells and sending messages from one area of the brain to another. This messaging process, known as excitation, is responsible for communicating what we see, what we smell, what we do, etc.
The other key type of cells are known as inhibitory cells, which are responsible for keeping the brain circuitry under control. If one area of the brain gets too excited and starts to receive too many signals at once, the inhibitory cells kick into gear and slow the process in order to restore balance.
“In terms of this form of epilepsy we’ve been studying, if a certain group of brain cells can’t communicate well through this inhibitory process, then (the animals) have seizures,” Huguenard said.
The protein DBI is a crucial component of the inhibitory process, as it boosts the actions of an important neurotransmitter called gamma-aminobutyric acid (GABA). Roughly one-fifth of the inhibitory nerve cells in the brain operate by secreting GABA, which binds to receptors located on excitatory cells, rendering them temporarily unable to fire any more electrical signals.
Without DBI, GABA cannot be enhanced, and the excitatory cells ultimately don’t get the message telling them to calm down. However, up until now, this function of DBI was not well understood by researchers.
To determine exactly how DBI operates in the brains of mammals, Huguenard and his team analyzed a group of bioengineered mice with the DBI gene mutation, meaning their brains were incapable of producing DBI.
“When we tested seizures in these animals and tested communication, we found that (the inhibitory process) was ineffective and that the animals had more seizures,” Huguenard said. “It told us that this gene is producing a product in the brain that is controlling the seizures.”
When they re-introduced the DBI-gene back into the brains of these mice, GABA-induced inhibition was restored and the mice suffered from fewer seizures.
Benzodiazepine drugs, like Valium, work in a very similar way to DBI by also enhancing GABA-induced inhibition. But they often come at a high cost. Many who take these medications long-term develop a physical dependence on the drug, experiencing serious withdrawal symptoms if they cease taking it. Some studies have also found Valium to have an adverse effect on both short-term and long-term cognition.
While the researchers only examined the brains of mice, they are optimistic DBI exists similarly in the brains of humans as well. If the results end up translating to the human mind, Huguenard hopes to find a way to naturally boost DBI in the brain, negating the need for Valium to help control seizures.
“The ultimate goal would be to develop new lines of therapy that would take this general approach – taking the brain’s mechanism for dealing with seizures and making them even more effective,” Huguenard said.
The research was published May 30 in the journal Neuron.
Finding a family for a pair of orphan receptors in the brain
Researchers at Emory University have identified a protein that stimulates a pair of “orphan receptors” found in the brain, solving a long-standing biological puzzle and possibly leading to future treatments for neurological diseases.
The results are published in the Proceedings of the National Academy of Sciences, Early Edition.
The human genome is littered with orphans: proteins that look like they will bind and respond to a hormone or a brain chemical, based on the similarity of their sequences to other proteins. However, scientists haven’t figured out what each orphan’s partner chemical is yet.
Orphans that look like GPCRs (G protein-coupled receptors) currently number about 100. GPCRs are the targets of many drugs and are involved in vision, smell and brain cells’ responses to a host of hormones and neurotransmitters. One orphan GPCR, called GPR37, has attracted interest from researchers because it is connected with an inherited form of Parkinson’s disease. It is abundant in the dopamine-producing neurons that degenerate in Parkinson’s. But its partner chemical, or “ligand,” has not been found.
"We reasoned that GPR37 had to be doing something important, besides becoming misfolded in some forms of Parkinson’s," says senior author Randy Hall, PhD, professor of pharmacology at Emory University School of Medicine.
Working with Hall, graduate student Rebecca Meyer devised a way to detect when cells producing GPR37 were reacting with GPR37’s ligand.
"Usually, cells remove GPCRs from their surfaces when they encounter their ligand," Meyer says. "So we set things up so that GPR37 would be labeled red on the surface of the cell, but would appear green once internalized."
They discovered that cells producing GPR37 – and also a close relative, GPR37L1 — respond to a protein known as prosaposin, which was discovered by John O’Brien of University of California San Diego in the 1990s.
Prosaposin is a growth factor for brain cells and protects them from stress. Scientists studying it had worked out that it stimulates cells via a GPCR – but which one was unclear until now. In animal models, prosaposin has shown potential for treating conditions such as stroke, Parkinson’s and neuropathic pain. An artificial fragment of prosaposin called prosaptide has been tested in clinical studies, but it quickly breaks down in the body.
"That’s the reason why it was so important to find the receptor," Hall says. "Then we can actually do some pharmacology."
Now, Hall’s laboratory is planning to look for other compounds that can activate GPR37 as well. These could be more stable in the body than the previously studied protein fragment and thus better potential drugs.
Doctors have reported a few cases of genetic deficiency in prosaposin, leading to severe neurodegeneration. Mice engineered to lack GPR37 have more subtle brain perturbations, so Hall also plans to test the hypothesis that prosaposin acts by both GPR37 and GPR37L1, by “knocking out” both in mice, potentially duplicating the same severe effects seen in the human cases of prosaposin deficiency.
Highly developed antennae containing different types of olfactory receptors allow insects to use minute amounts of odors for orientation towards resources like food, oviposition sites or mates. Scientists at the Max Planck Institute for Chemical Ecology in Jena, Germany, have now used mutant flies and for the first time provided experimental proof that the extremely sensitive olfactory system of fruit flies − they are able to detect a few thousand odour molecules per millilitre of air, whereas humans need hundreds of millions − is based on self-regulation of odorant receptors. Even fewer molecules below the response threshold are sufficient to amplify the sensitivity of the receptors, and binding of molecules shortly afterwards triggers the opening of an ion channel that controls the fly’s reaction and flight behaviour. This means that a below threshold odor stimulation increases the sensitivity of the receptor, and if a second odour pulse arrives within a certain time span, a neural response will be elicited.
It is amazing how many fruit flies (Drosophila melanogaster) find their way to a rotting apple. It is known that insects are able to detect the slightest concentrations of odour molecules, especially pheromones, but also “food signals”.
Dieter Wicher, Shannon Olsson, Bill Hansson and their colleagues at the Max Planck Institute for Chemical Ecology were looking for answers to the question why insects can trace odour molecules so easily and at such low concentrations in comparison to other animals. They focused their attention on odorant receptor proteins in the antenna, the insects’ nose. These insect proteins are pretty young from an evolutionary perspective and their molecular constituents may be the basis for the insects’ highly sensitive sense of smell.
Insect odorant receptors form a receptor system that consists of the actual receptor protein and an ion channel. After binding of an odour molecule, receptor protein and ion channel trigger the neural electrical response. This mechanism was recently described in the receptor system Or22a-Orco. Apart from functioning as so-called ionotropic receptors, which enable ion flow through membranes after binding of odour molecules, odorant receptors also elicit intracellular signals. These stimulate the formation of cyclic adenosine monophosphate (cyclic AMP or cAMP), which activates an ion flow through the co-receptor Orco. The role and relevance of this weak and slow electrical current, however, was until now unclear.
Merid N. Getahun, a PhD student from Ethiopia, and his colleagues have conducted numerous experiments on Drosophila olfactory neurons. They injected tiny amounts of compounds that stimulate, inhibit or imitate cAMP formation directly into the sensory hairs housing olfactory sensory neurons on the fly antenna. The researchers tested the flies’ responses to ethyl butyrate, which has a fruity odour similar to pineapple, and measured activity in the sensory neurons by using glass microelectrodes. As a control, they used genetically modified fruit flies where the co-receptor Orco had been inactivated. “The fact that these mutants are no more able to respond to cAMP or the inhibition/activation of the involved key enzymes, such as protein kinase C and phospholipase C, shows that the highly sensitive olfactory system in insects is regulated intracellularly by their own odorant receptors,” says Dieter Wicher, the leader of the research group.
The combination of odorant receptor and co-receptor Orco can be compared to a transistor, Wicher continues: A weak basic current is sufficient to release the main electric current that activates the neuron. The process can also be seen as a short-term memory situated in the insect nose. A very weak stimulus does not elicit a response when it first occurs, but if it reoccurs within a certain time span it will release the electrical response according to the principle “one time is no time, but two is a bunch.”
Human cognition depends upon slow-firing neurons
Good mental health and clear thinking depend upon our ability to store and manipulate thoughts on a sort of “mental sketch pad.” In a new study, Yale School of Medicine researchers describe the molecular basis of this ability — the hallmark of human cognition — and describe how a breakdown of the system contributes to diseases such as schizophrenia and Alzheimer’s disease.
“Insults to these highly evolved cortical circuits impair the ability to create and maintain our mental representations of the world, which is the basis of higher cognition,” said Amy Arnsten, professor of neurobiology and senior author of the paper published in the Feb. 20 issue of the journal Neuron.
High-order thinking depends upon our ability to generate mental representations in our brains without any sensory stimulation from the environment. These cognitive abilities arise from highly evolved circuits in the prefrontal cortex. Mathematical models by former Yale neurobiologist Xiao-Jing Wang, now of New York University, predicted that in order to maintain these visual representations the prefrontal cortex must rely on a family of receptors that allow for slow, steady firing of neurons. The Yale scientists show that NMDA-NR2B receptors involved in glutamate signaling regulate this neuronal firing. These receptors, studied at Yale for more than a decade, are responsible for activity of highly evolved brain circuits found especially in primates.
Earlier studies have shown these types of NMDA receptors are often altered in patients with schizophrenia. The Neuron study suggests that those suffering from the disease may be unable to hold onto a stable view of the world. Also, these receptors seem to be altered in Alzheimer’s patients, which may contribute to the cognitive deficits of dementia.
The lab of Dr. John Krystal, chair of the department of psychiatry at Yale, has found that the anesthetic ketamine, abused as a street drug, blocks NMDA receptors and can mimic some of the symptoms of schizophrenia. The current study in Neuron shows that ketamine may reduce the firing of the same higher-order neural circuits that are decimated in schizophrenia.
“Identifying the receptor needed for higher cognition may help us to understand why certain genetic insults lead to cognitive impairment and will help us to develop strategies for treating these debilitating disorders,” Arnsten said.
Stopping cold: USC scientists turn off the ability to feel cold
USC neuroscientists have isolated chills at a cellular level, identifying the sensory network of neurons in the skin that relays the sensation of cold.
David McKemy, associate professor of neurobiology in the USC Dornsife College of Letters, Arts and Sciences, and his team managed to selectively shut off the ability to sense cold in mice while still leaving them able to sense heat and touch.
In prior work, McKemy discovered a link between the experience of cold and a protein known as TRPM8 (pronounced trip-em-ate), which a sensor of cold temperatures in neurons in the skin, as well as a receptor for menthol, the cooling component of mint. Now, in a paper appearing in the Journal of Neuroscience on February 13, McKemy and his co-investigators have isolated and ablated the neurons that express TRPM8, giving them the ability to test the function of these cells specifically.
Using mouse-tracking software program developed by one of McKemy’s students, the researchers tested control mice and mice without TRPM8 neurons on a multi-temperature surface. The surface temperature ranged from 0 degrees to 50 degrees Celsius (32 to 122 degrees Farenheit), and mice were allowed to move freely among the regions.
The researchers found that mice depleted of TRPM8 neurons could not feel cold, but still responded to heat. Control mice tended to stick to an area around 30 degrees Celsius (86 degrees Fahrenheit) and avoided both colder and hotter areas. But mice without TRPM8 neurons avoided only hotter plates and not cold — even when the cold should have been painful or was potentially dangerous.
In tests of grip strength, responses to touch, or coordinated movements, such as balancing onto a rod while it rotated, there was no difference between the control mice and the mice without TRPM8-expressing neurons.
By better understanding the specific ways in which we feel sensations, scientists hope to one day develop better pain treatments without knocking out all ability to feel for suffering patients.
"The problem with pain drugs now is that they typically just reduce inflammation, which is just one potential cause of pain, or they knock out all sensation, which often is not desirable," McKemy said. "One of our goals is to pave the way for medications that address the pain directly, in a way that does not leave patients completely numb."
In the brain, broken down ‘motors’ cause anxiety
When motors break down, getting where you want to go becomes a struggle. Problems arise in much the same way for critical brain receptors when the molecular motors they depend on fail to operate. Now, researchers reporting in Cell Reports, a Cell Press publication, on February 7, have shown these broken motors induce stress and anxiety in mice. The discovery may point the way to new kinds of drugs to treat anxiety and other disorders.
The study in mice focuses on one motor in particular, known as KIF13A, which, according to the new evidence, is responsible for ferrying serotonin receptors. Without proper transportation, those receptors fail to reach the surface of neurons and, as a result, animals show signs of heightened anxiety.
In addition to their implications for understanding anxiety, the findings also suggest that defective molecular motors may be a more common and underappreciated cause of disease.
"Most proteins are transported in vesicles or as protein complexes by molecular motors," said Nobutaka Hirokawa of the University of Tokyo. "As shown in this study, defective motors could cause many diseases."
Scientists know that serotonin and serotonin receptors are involved in anxiety, aggression, and mood. But not much is known about how those players get around within cells. When Hirokawa’s team discovered KIF13A at high levels in the brain, they wondered what it did.
The researchers discovered that mice lacking KIF13A show greater anxiety in both open-field and maze tests and suggest that this anxious behavior may stem from an underlying loss of serotonin receptor transport, which leads to a lower level of expression of those receptors in critical parts of the brain.
"Collectively, our results suggest a role for this molecular motor in anxiety control," the researchers wrote. Hirokawa says the search should now be on for anti-anxiety drug candidates aimed at restoring the brain’s serotonin receptor transport service.
Definitive proof for receptor’s role in synapse development
Jackson Laboratory researchers led by Associate Professor Zhong-wei Zhang, Ph.D., have provided direct evidence that a specific neurotransmitter receptor is vital to the process of pruning synapses in the brains of newborn mammals.
Faulty pruning at this early developmental stage is implicated in autism-spectrum disorders and schizophrenia. The definitive evidence for N-methyl-D-aspartate receptor (NMDAR) in pruning has eluded researchers until now, but in research published in the Proceedings of the National Academy of Sciences, Zhang’s lab had serendipitous help in the form of a mouse model containing brain cells lacking NMDAR side-by-side with cells containing the receptor.
Soon after birth, mammals’ brains undergo significant development and change. Initially, large numbers of synapses form between neurons. Then, in response to stimuli, the synaptic connections are refined—some synapses are strengthened and others eliminated, or pruned.
In most synapses, glutamate serves as the neurotransmitter, and NMDAR, a major type of post-synaptic glutamate receptor, was previously known to play an important role in neural circuit development. Previous research has implicated the importance of NMDARs in pruning, but it remained unclear whether they played a direct or indirect role.
Zhang and colleagues focused on the thalamus, a brain region where synapse pruning and strengthening can be monitored and quantified with relative ease. They got unexpected help when they realized the mouse model they were using had thalamus cells lacking NMDARs right next to cells with normal NMDAR levels.
The researchers showed that the refinement process was disrupted in the absence of NMDARs. At the same time, neighboring neurons with the receptors proceeded through normal synaptic strengthening and pruning, clearly establishing the necessity of NMDARs in postsynaptic neurons for synaptic refinement.
"Whenever I give a talk or meet colleagues," Zhang says, "the first question that comes up is whether the NMDA receptor is important. It’s good that this is now settled definitively."
There has been extensive research into synaptic strengthening, and most of these studies indicate that the presence of NMDARs may support the recruitment of larger numbers of another kind of glutamate receptor to strengthen the synaptic connections. How NMDARs regulate the pruning process remains largely unknown, however.
How Cells in the Nose Detect Odors
Now a team of scientists, led by neurobiologists at the University of California, Riverside, has an explanation. Focusing on the olfactory receptor for detecting carbon dioxide in Drosophila (fruit fly), the researchers identified a large multi-protein complex in olfactory neurons, called MMB/dREAM, that plays a major role in selecting the carbon dioxide receptors to be expressed in appropriate neurons.
Study results appear in the Nov. 15 issue of Genes & Development. The research is featured on the cover of the issue.
According to the researchers, a molecular mechanism first blocks the expression of most olfactory receptor genes (~60) in the fly’s antennae. This mechanism, which acts like a brake, relies on repressive histones —proteins that tightly wrap DNA around them. All insects and mammals are equipped with this mechanism, which keeps the large families of olfactory receptor genes repressed.
“How, then, do you release this brake so that only the carbon dioxide receptor is expressed in the carbon dioxide neuron while the remaining receptors are repressed?” said Anandasankar Ray, an assistant professor of entomology, whose lab conducted the research. “Our lab, in collaboration with a lab at Stanford University, has found that the MMB/dREAM multi-protein complex can act on the genes of the carbon dioxide receptors and de-repress the braking mechanism — akin to taking the foot off the brake pedal. This allows these neurons to express the receptors and respond to carbon dioxide.”
Ray explained that one way to understand the mechanism in operation is to consider a typewriter. When none of the keys are pressed, a spring mechanism or “brake” can be imagined to hold the type bars away from the paper. When a key is pressed, however, the brake on that key is overcome and the appropriate letter is typed onto the paper. And just as typing only one letter in one spot is important for each letter to be recognized, expressing one receptor in one neuron lets different sensor types to be generated in the nose.