 locked into one of its binding pockets.)
Two studies have decoded the structure of two of the brain's serotonin receptors. Here shown is a receptor known as 1B with the migraine drug ergotamine (pink) locked into one of its binding pockets.
Image: Chong Wang & Huixian Wu
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Researchers have deciphered the molecular structures of two of the brain's crucial lock-and-key mechanisms. The two molecules are receptors for the natural neurotransmitter serotonin — which regulates activities such as sleep, appetite and mood — and could provide targets for future drugs to combat depression, migraines or obesity.
“This is huge,” says Bryan Roth, a neuropharmacologist at the University of North Carolina Chapel Hill Medical School, and a co-author of the two studies published in Science today. “Before this there was no crystal structure for any serotonin receptor. A lot of what was theoretical is now known with a great degree of certainty,” he says.
Scientists have been trying to decipher serotonin receptors for years. Armed with information on the atomic level, they might now be able to make breakthroughs in drug discovery and in understanding how the physical structures of the brain produce consciousness, says Roth.
Christoph Anacker, a neuropharmacologist at King's College London, agrees that the findings are important for drug discovery. “These receptors are involved in so many conditions, especially depression, and knowing the molecular structures will help to develop more specific drugs and avoid the expression of undesired side effects.”
Chemical messengers
There are 14 different known serotonin receptors. The molecules lie on the outer membranes of nerve cells; when drugs or neurotransmitters lock into the receptors from outside the cell, they trigger the release of other chemicals inside the cell. Those chemicals — which can be different depending on what drug or neurotransmitter has triggered them — activate further hormones and metabolites, producing signaling cascades that are ultimately responsible for many aspects of the way we feel, perceive and behave.
Some drugs bind at more than one receptor, setting off not-fully-understood reactions that can produce unwanted side effects. To avoid this, researchers want to fine-tune drugs so that they activate only the desired signaling pathway.
Roth and his colleagues uncovered the receptor structures using X-ray crystallography, in which X-ray beams are fired at crystals of the compound, and the structure is deduced from how the beams scatter.
The teams focused on two receptors, called 1B and 2B. They found that the molecules had very similar structures in the areas where serotonin docks.
But in one area of the 1B receptor, the binding pocket was wider than in the 2B receptor. Although the difference was a mere 0.3 nanometers, about the width of three helium atoms, the difference is enough to explain why the two receptors bind differently to certain compounds.
This distinction may be relevant to drug safety: some drugs that activate the 2B receptor have been thought to cause heart problems, and have been withdrawn as unsafe. The connection has earned the 2B the nickname of death receptor.
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6 Comments
Add CommentIf pharma had to compete with natural medicine ,fairly, pharma would suffer a quick death
Reply | Report Abuse | Link to thisalan6302- People with your ignorance make me angry......you clearly fail to have comprehension of the scientific process. Advocates of natural medicine fail to acknowledge that for all the years these medicines were around (pre modern medicine and pharmacology) that the age at death was young and amount of suffering was very high....despite all these wonderful natural products that our ancestors, ancient Chinese, -----fill in the blank.......had access too.
Reply | Report Abuse | Link to thisI have seen many things change in even the past 30 years of my clinical practice, including many people with signficant depression who were helped live happier lives by modern SSRI's which were a huge improvement over older antidepressants. St. Johns Wort cannot compare one bit to the efficacy of the specifically desgined medications and obviously the article is describing the next evolution since we do not always know which medication is best for which patient yet......science is not all knowing but it is progressive. Sadly the natural health market just peddles a new product with the same old hype every year or two....and yes "Big" natural medicine industry makes billions of dollars bilking trusting people out of their dough, usually for ineffective products.
Please go do some more research before spouting your biased view on a scientific forum.......although usually people like you do not want to know the "truth" since it is preferable to have a simplistic view that Big Pharma is bad for you.......tell that to my depressed patients who are back at work and enjoying life after medication (and yes many of them did try natural products first).
agreed!
Reply | Report Abuse | Link to thisAs a person that tried "natural solutions" before prescribed medicines, I can honestly say that Chamomile, Valerian root and St. John's Wort were only mildly helpful. The prescription drugs were an unpleasant crap shoot for the first 4 tries but Zoloft has made a huge difference and I'm pretty near non-functional without it.
Reply | Report Abuse | Link to thisThanks for your insight....yes not all prescribing is smooth for sure.....some people go on the first medication and think it is great and others, like yourselves, have a bit more of a trial.......which is hopefully why increasing knowledge can better identify the subsets of patients that will do better with specific drugs (and hopefully also have fewer side effects). I always recall a patient who had been an natural products advocate his whole life........when he went on Paxil at age 55 he made an interesting observation: "I wish I had been on this drug since age 16 and my life would have been a whole lot less cloudy"......this man was a successful film producer and generally considered a very pleasant and educated man.......however he had lived with the demons of chronic depression underlying his life.......he was frankly utterly amazed at the change in his functioning on Paxil....clearly it improved something in his brain chemistry.......quite gratifying as a physician to see but also somewhat saddening to think this man had lived a less than full life because of his condition.
Reply | Report Abuse | Link to thisNew anti-mania meds are also needed. Maybe the same methods will have results here,too. I hope and pray!
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