Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:

 

Scientists identify molecular step that causes intoxication

12.12.2003


Scientists at UCSF’s Ernest Gallo Clinic and Research Center have identified a single brain protein that can account for most of the intoxicating effects of alcohol. The finding pinpoints perhaps the best target yet for a drug to block alcohol’s effect and potentially treat alcoholism, the scientists say.



The mechanisms by which alcohol acts on the brain are thought to be similar throughout the animal kingdom, since species from worms and fruit flies to mice and humans all become intoxicated at similar alcohol concentrations. But although studies have identified a number of genes that can partially influence how alcohol affects behavior, this is the first finding that a single gene and the brain protein it codes for - known as an ion channel - are responsible for the intoxicating effects of alcohol in a living organism, according to the researchers.

The discovery was made in a six-year research effort focusing on Caenorhabditis elegans, the roundworm widely studied because about half of its approximately 20,000 genes have counterparts in the human genome.


"We have found that alcohol acts on this channel in nerve cells to cause neural depression and intoxication," said Steven McIntire, MD, PhD. "We would expect that the same process functions in humans, who also have this type of channel." McIntire is senior author of a report on the discovery in the December 12 issue of the journal CELL. He is assistant professor of neurology at UCSF and principal investigator at the UCSF-affiliated Gallo Clinic and Research Center.

Researchers already knew that the gene known as slo-1 codes for a channel-like protein in the brain that can allow potassium ions to pour out of neurons, a normal process that temporarily slows down the neuron’s activity. In the study, the scientists discovered that alcohol makes the channel open more frequently, depressing neuron activity and leading to sluggish, uncoordinated movement typical of intoxication.

The same kind of channel - known as the BK channel - is found in the human brain, the researchers say, suggesting that a drug that modifies alcohol’s effect on the channel could quickly sober someone up after a bout of drinking, or weaken the taste for alcohol among people vulnerable to alcoholism.

"Until we conduct human studies, we can’t say for sure whether this channel or the pathways involving this channel are defective in alcoholics, but this is a highly attractive target. We now know it is central to the intoxicating effect of alcohol," McIntire said. Studies of BK channels in cell culture suggest that the human BK channel is affected in the same way, he added.

After identifying the role of the slo-1 gene, the scientists were able to show that worms lacking this one gene were virtually unaffected by alcohol, often behaving normally even when exposed to alcohol doses that would leave normal animals comatose.

"Alcohol has a diffuse effect, and it certainly acts at other sites as well," McIntire said. "Studies have shown that altering one gene or another can partially affect behavioral responses to ethanol. But this is the first study to demonstrate that a single gene mutation can create such strong resistance to the behavioral effect of ethanol."

The channel studied by McIntire and his colleagues, technically known as the BK potassium channel, is one of more than 200 known channels that regulate cell activities by controlling the flow of charged atoms, or ions, in and out of the cell. BK channels are active in nerve, muscle and gland tissue in mammals, where they control neurotransmitter release, muscle contraction and hormonal secretion, the scientists report. The channel may be involved in hormonal or non-behavioral effects of ethanol as well.

If alcohol activation of the BK channel is the major cause of intoxication, then artificially activating the channel without alcohol should also produce the intoxicating effect, the scientists reasoned. They identified mutants in which the BK channels opened more often than usual - without alcohol exposure - just as normal channels do when exposed to alcohol. As they predicted, worms with these abnormal BK channels acted just as intoxicated - without any exposure to alcohol - as normal worms did under the influence, confirming the new finding.

The research began with a search for genes that account for alcohol’s intoxicating effect. The scientists treated the microscopic worms with chemicals that cause mutations and result in mutant offspring. They then screened thousands of different mutants for how they moved when exposed to alcohol, and thousands of others for their ability to lay eggs in the presence of ethanol. From this process, they identified eight genetic variants that showed varying degrees of resistance to the effects of alcohol on locomotion. Only those with mutated slo-1 genes were extremely resistant to alcohol.

The research showed that the alcohol-resistance trait was due to slo-1 genes in neurons, as opposed to other cells such as muscle. Then, using standard electrophysiological techniques, the scientists determined that alcohol activates the BK potassium channel in the living animals, inhibiting neuronal action and leading to the decreased speed and motor control. BK channel mutants, on the other hand - worms that either lacked the channels or had non-functional ones - were virtually immune to the effects of alcohol.

The scientists conclude that the BK channel is the major physiological mediator of ethanol intoxication in C. elegans. More important, if BK channels mediate alcohol effects, they write, then the "near-ubiquitous" presence of BK channels in mammals may explain the varied effects of alcohol on people as well.

"Identifying the molecules in the brain that alcohol acts on to change behavior will allow us to pursue a direct approach to develop drugs or other therapies to treat alcohol addiction," McIntire says.

Collaborators in the research and co-authors on the CELL paper are Andrew G. Davies, PhD, senior scientist; Jonathan T. Pierce-Shimomura, PhD, and Hongkyun Kim, PhD, both post-doctoral scientists; and Tod R. Thiele, BS, research assistant, all in McIntire’s lab; Antonello Bonci, MD, UCSF assistant professor of neurology; Cornelia I. Bargmann, PhD, UCSF professor of anatomy; and Miri K. VanHoven, a graduate student in Bargmann’s lab.


The Gallo Center research was supported by the National Institutes of Health, the Department of Defense and by funds provided by the State of California for medical research on alcohol and substance abuse through the University of California, San Francisco.

Wallace Ravven | EurekAlert!
Further information:
http://www.ucsf.edu/

More articles from Life Sciences:

nachricht How brains surrender to sleep
23.06.2017 | IMP - Forschungsinstitut für Molekulare Pathologie GmbH

nachricht A new technique isolates neuronal activity during memory consolidation
22.06.2017 | Spanish National Research Council (CSIC)

All articles from Life Sciences >>>

The most recent press releases about innovation >>>

Die letzten 5 Focus-News des innovations-reports im Überblick:

Im Focus: Can we see monkeys from space? Emerging technologies to map biodiversity

An international team of scientists has proposed a new multi-disciplinary approach in which an array of new technologies will allow us to map biodiversity and the risks that wildlife is facing at the scale of whole landscapes. The findings are published in Nature Ecology and Evolution. This international research is led by the Kunming Institute of Zoology from China, University of East Anglia, University of Leicester and the Leibniz Institute for Zoo and Wildlife Research.

Using a combination of satellite and ground data, the team proposes that it is now possible to map biodiversity with an accuracy that has not been previously...

Im Focus: Climate satellite: Tracking methane with robust laser technology

Heatwaves in the Arctic, longer periods of vegetation in Europe, severe floods in West Africa – starting in 2021, scientists want to explore the emissions of the greenhouse gas methane with the German-French satellite MERLIN. This is made possible by a new robust laser system of the Fraunhofer Institute for Laser Technology ILT in Aachen, which achieves unprecedented measurement accuracy.

Methane is primarily the result of the decomposition of organic matter. The gas has a 25 times greater warming potential than carbon dioxide, but is not as...

Im Focus: How protons move through a fuel cell

Hydrogen is regarded as the energy source of the future: It is produced with solar power and can be used to generate heat and electricity in fuel cells. Empa researchers have now succeeded in decoding the movement of hydrogen ions in crystals – a key step towards more efficient energy conversion in the hydrogen industry of tomorrow.

As charge carriers, electrons and ions play the leading role in electrochemical energy storage devices and converters such as batteries and fuel cells. Proton...

Im Focus: A unique data centre for cosmological simulations

Scientists from the Excellence Cluster Universe at the Ludwig-Maximilians-Universität Munich have establised "Cosmowebportal", a unique data centre for cosmological simulations located at the Leibniz Supercomputing Centre (LRZ) of the Bavarian Academy of Sciences. The complete results of a series of large hydrodynamical cosmological simulations are available, with data volumes typically exceeding several hundred terabytes. Scientists worldwide can interactively explore these complex simulations via a web interface and directly access the results.

With current telescopes, scientists can observe our Universe’s galaxies and galaxy clusters and their distribution along an invisible cosmic web. From the...

Im Focus: Scientists develop molecular thermometer for contactless measurement using infrared light

Temperature measurements possible even on the smallest scale / Molecular ruby for use in material sciences, biology, and medicine

Chemists at Johannes Gutenberg University Mainz (JGU) in cooperation with researchers of the German Federal Institute for Materials Research and Testing (BAM)...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

Event News

Plants are networkers

19.06.2017 | Event News

Digital Survival Training for Executives

13.06.2017 | Event News

Global Learning Council Summit 2017

13.06.2017 | Event News

 
Latest News

Quantum thermometer or optical refrigerator?

23.06.2017 | Physics and Astronomy

A 100-year-old physics problem has been solved at EPFL

23.06.2017 | Physics and Astronomy

Equipping form with function

23.06.2017 | Information Technology

VideoLinks
B2B-VideoLinks
More VideoLinks >>>