A key question in protein biochemistry is how proteins recognize "correct" interaction partners in a sea of cellular factors. Nowhere is that more critical to know than in the brain, where interactions governing channel protein activity can alter an organism's behavior. A team of biologists at the Salk Institute for Biological Studies has recently deciphered a molecular code that regulates availability of a brain channel that modulates neuronal excitability, a discovery that might aid efforts to treat drug addiction and mental disorders.
In the this week's Online Early Edition of the Proceedings of the National Academy of Sciences, Paul Slesinger, Ph.D., Associate Professor in the Clayton Foundation Laboratories for Peptide Biology, and colleagues detail how a regulatory factor called SNX27 distinguishes a brain channel protein called GIRK (short for G-protein-coupled inwardly rectifying potassium channels) from structurally similar proteins and then targets it for destruction.
That work extends the group's 2007 study showing that when SNX27 proteins capture GIRK channels, reducing the number of channels at their rightful destination, the cell membrane. "We were curious about what determined the selectivity of this interaction," says Slesinger. "We knew that SNX27 interacted with a structural motif found on GIRK channels but many channel proteins display a similar motif. We wanted to know what allowed SNX27 to specifically choose GIRK channels."
Knowing this is critical because of the connection of GIRK channels to substance abuse. Slesinger and others have shown that alcohol or club drugs linked to sexual assault (GHB) affects GIRK channel function in the brain. Loss-of-inhibition behaviors associated with abuse of these substances result from the fact that GIRK channels allow potassium ions to leak out of a stimulated neuron, thereby dampening a cell's excitability.
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