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Exploring Tiny Nooks Inside Cell Receptors: Leading Toward New Treatments for Addiction?
Alcohol and drugs of abuse such as cocaine and methamphetamines are well known to alter the normal workings of the human brain. For scientists like Brain & Behavior Research Foundation Grantee Paul A. Slesinger, Ph.D., understanding the precise way in which this interference occurs is the key to developing a new wave of highly specific treatments to control the effects of substance abuse.
One way in which drugs and alcohol perturb the brain is by interfering with the normal process of cell-to-cell communication. Such communication - the transmission of signals that cause neurons to fire or cease firing - is partly regulated by the action of ion channels found on the outer surfaces, or membranes, of nerve cells. Dr. Slesinger, an associate professor at the Salk Institute for Biological Studies in California, leads a team that has recently published a study funded partly by a NARSAD Grant that lays bare the inner workings of a particular channel type that is implicated in the disturbances caused by abused drugs and alcohol.
Previously, Dr. Slesinger and colleagues had discovered how ethanol, the active molecule in alcohol, directly interacts with a specific "nook" - a tiny structural feature - located inside pore-like channels that allow charged molecules of potassium to enter and exit nerve cells. These ion channels are called GIRKs.
The team's newly published study adds vital new detail to their emerging picture of GIRKs - in this case, a picture of how GIRK channels migrate from the innards of a nerve cell to positions on the cell membrane, and then back. A protein called SNX27 is a key regulator of the number of at least some types of GIRKs (there are several varieties), and thus their level of activity. The new study reveals precisely how SNX27 associates with GIRKs.
It was known that a "motif" on GIRK channels consisting of several bits of information was critical in the process. "This motif can be likened to a zip code," Dr. Slesinger says. "And what our new work shows is that this zip code is more complicated than previously thought. It's something like a letter not being deliverable unless you add the extra four-digit code to the regular zip code of your intended recipient. In this case, the 'motif,' we found, consists of two extra 'digits' (they are actually amino acids) beyond the previously known 'zip code.'"