Paul A. Slesinger
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.
"Drugs of abuse can produce long-term changes in the electrical activity of neurons in the brain. Recently, we have been researching a new role for Girk potassium channels—proteins that control the movement of potassium ions in the brain—in drug addiction. Our studies may provide new insights into the cellular mechanisms of drug addiction as well as some mental disorders, such as schizophrenia and attention deficit hyperactivity disorder (ADHD)."
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.
Left to right:
Michaelanne Munoz, Bartosz Balana, Claire Padgett, Natalie Taylor, Prafulla Aryal, Debbie Doan, Laia Bahima Borras, Paul Slesinger
Salk News Releases
Speeding up drug discovery with rapid 3D mapping of proteins
May 29, 2012
Discovery of brain's natural resistance to drugs may offer clues to treating addiction
March 7, 2012
Salk scientists crack molecular code regulating neuronal excitability
March 21, 2011
Site for alcohol's action in the brain discovered
June 28, 2009
A drug-sensitive "traffic cop" tells potassium channels to get lost
September 4, 2007
Doing nature one better: Expanding the genetic code in living mammalian cells
July 2, 2007
Elastic Gateway in Ion Channel Discovered
March 24, 2005
It's the Dosage: Salk Study Shows How Drugs of Abuse Work
February 25, 2004
Awards and Honors
- Alfred P. Sloan Research Fellow 1998-2000
- McKnight Scholars Award in Neuroscience 1999-2002
- Basic Sciences Faculty Teaching Award, Neurosciences at UCSD 2000-2001
- Human Frontiers Science Program Young Investigator Grant 2001-2004
- McKnight Technological Innovations in Neuroscience Award 2003-2005
- National Alliance for Research on Schizophrenia and Depression Independent Investigator Award 2006-2008