21 August 2006

Important New Neuro-Research Tool--From the Sea

Experimental research in biology and pharmacology proceeds with the discovery of new research tools. Recently, University of Utah researchers discovered a new tool for research into an important neuroreceptor--the nicotinic Acetylcholine receptor. This receptor plays a critical role in the brain, muscle, and autonomic ganglia. This new tool promises to help find new treatments for neurological and neuromuscular diseases that currently cause large scale misery.

University of Utah researchers isolated an unusual nerve toxin in an ocean-dwelling snail, and say its ability to glom onto the brain's nicotine receptors may be useful for designing new drugs to treat a variety of psychiatric and brain diseases.

"We discovered a new toxin from a venomous cone snail that may enable scientists to more effectively develop medications for a wide range of nervous system disorders including Parkinson's disease, Alzheimer's disease, depression, nicotine addiction and perhaps even schizophrenia," says J. Michael McIntosh.

Discovery of the new cone snail toxin will be published Friday, Aug. 25 in The Journal of Biological Chemistry by a team led by McIntosh, a University of Utah research professor of biology, professor and research director of psychiatry, member of the Center for Peptide Neuropharmacology and member of The Brain Institute.

.... McIntosh says the OmIA toxin will be useful in designing new medicines because it fits like a key into certain lock-like "nicotinic acetylcholine receptors" found on nerve cells in the brain and the rest of the nervous system.

"Those are the same types of receptors you activate if you smoke a cigarette," he says, explaining that nicotine in cigarette smoke "binds" to the receptor to trigger the release of a neurotransmitter, which is a chemical that carries a nerve impulse from one nerve cell to another, allowing nerve cells to communicate.

"Nicotine acts on those receptors in our brain, but they are in our brain for better reasons than to enjoy a cigarette," McIntosh says. Different forms or subtypes of nicotinic receptors control the release of different neurotransmitters. "That's important because if you had compounds to facilitate the release of one neurotransmitter and not another neurotransmitter, that opens up medicinal potential," he says.

"For instance, one receptor modifies the release of dopamine. There are inadequate amounts of dopamine in Parkinson's disease," so a medicine designed to fit into a certain subtype of nicotinic receptor would produce more dopamine and thus protect against the development of tremors and other Parkinson's symptoms. Indeed, other studies have found that smoking seems to forestall Parkinson's disease.

A medicine that could block certain nicotinic receptors could be used to help people stop smoking cigarettes, and the same method might work for alcoholism because nicotinic receptors may be involved in alcohol addiction, McIntosh says.

Other nicotinic receptors trigger the release of neurotransmitters involved in memory, so activating the right receptors might lessen Alzheimer's memory loss.

"One reason people smoke is they feel their thinking may be a little better, with increased attention and focus," McIntosh says, noting that pharmaceutical companies "would like to mimic that positive benefit without all the downsides of cigarette smoke."

Other nicotinic receptors influence "the release of serotonin and norepinephrine, two neurotransmitters strongly implicated in mood disorders" such as depression, so a drug to activate those receptors might treat depression, he adds.

Schizophrenics tend to smoke heavily because something in cigarette smoke "seems to help them filter out irrelevant stimuli. They can focus better," McIntosh says. So a drug aimed at certain nicotinic receptors might treat schizophrenia.

....he snails from which the new toxin was obtained were collected by divers in Olivera's native Philippines. Venomous snails use a dart-like tooth to zap fish, snails and other prey, injecting them with an immobilizing toxin. Venom from the collected snails was extracted at a lab in the Philippines, and then sent to Utah.

Once the screening process identified OmIA as promising, McIntosh and colleagues purified the toxin – one of perhaps 200 components in Conus omaria venom. They determined its chemical structure and then synthesized more of the toxin, since they had only a small amount of the natural version.

Next, the synthetic toxin was tested to see how well it acted as a "key" to fit into the "locks" represented both by binding proteins (from freshwater snails and a sea slug) and by actual nicotinic receptors, which came from rat cells but were grown in frog eggs. That allowed the researcher to grow various subtypes of the nicotinic receptors and see how well the toxin fit them.

Taylor and Han provided pictures of the physical structures of the binding protein "locks" and toxin "key," and then "used computer simulation to dock the two structures together," says McIntosh. "That generates a picture of the binding site – the points of contact between the toxin and the binding protein."

The site is the place a new drug would be designed to fit.

"The whole idea is to make the model of the nicotinic receptor so predictive that you can then really speed up the development of drugs," McIntosh says. "If you have an accurate model of the receptor, you can plug in a model of your drugs and do a lot of 'virtual screening.' Rather than synthesizing a million compounds and having all but one be duds, you can synthesize a few thousand compounds based on the model and come up with a better drug with less time and resources."

It is nice to find new drugs, and new classes of drugs, from nature. Finding a new research tool is even better, since new research tools can lead to new drugs, new classes of drugs, even new approaches to an entire field of study.

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