Clayton Foundation Laboratories for Peptide Biology
Nerve cells communicate by sending electrical impulses along their axons, long, hair-like extensions that reach out to neighboring nerve cells. These impulses involve the opening and closing of ion channels and allow ions – electrically charged atoms – or small molecules to enter or leave the cell. The flow of these ions creates an electrical current that produces tiny voltage changes across the membrane. In his quest to understand how brain cells communicate, Dr. Paul A. Slesinger, Associate professor in the Clayton Foundation Laboratories for Peptide Biology, focuses on one particular type of channel that allows potassium ions to cross the cell membrane.
Slesinger's research ranges from studies on the molecular details of how potassium ion channels open and close to a cellular level on the role potassium channels have in nerve cell signaling. Recent studies in the lab have also turned to investigating the role of potassium channels in drug addictions and mental disorders. Drugs can significantly alter the actions of nerve cell receptors and channels. Slesinger and his team are now looking at how to selectively manipulate the receptors and/or channels and at the cell signaling pathways that lead to addictions. They are also studying other parts of the brain, where these receptors and potassium channels may play a role in memory and other mental functions.
Alcohol's inebriating effects are familiar to everyone. But despite its long history and the widespread use of ethanol–the alcohol in intoxicating beverages–when it comes to alcohol's impact on brain activity on a molecular level, it remains among the least understood of psychoactive drugs. Although alcohols had previously been shown to lead to the opening of GIRK (short for G-protein-activated inwardly rectifying potassium) channels, it was not known whether this was a direct effect or byproduct of other molecular changes in the cell.
When Slesinger and collaborators determined the threedimensional structure of GIRK channels at high resolution, they discovered a molecular pocket that resembled confirmed alcohol-binding sites found in two other proteins (alcohol dehydrogenase, the enzyme that breaks down alcohol in the body, and LUSH, a fruit fly protein that senses alcohol in the environment). This finding allowed them to address the puzzle of how alcohol activates GIRK channels.
When they systematically introduced amino acid substitutions that denied alcohol molecules access to the potential interaction site, alcohol could no longer efficiently activate the channel, confirming that they had hit upon an important regulatory site for alcohol. The team further established that this pocket is a trigger point for channel activation since G protein activation was also altered. They believe that alcohol hijacks the intrinsic activation mechanism of GIRK channels and stabilizes the opening of the channel, perhaps by "lubricating" the channel's activation "gears."
A better understanding of how GIRK channels are activated could point to new strategies for treating human diseases. Using the protein structure as a starting point, for example, it may be possible to develop a drug that antagonizes the actions of alcohol to treat alcohol dependence. Alternatively, if a novel drug is identified that fits the alcohol-binding site and activates GIRK channels, this could dampen overall neuronal excitability in the brain and perhaps provide a novel pharmacological tool for treating epilepsy.