One of alcohol's key gateway to the brain identified

Scientists have used a rare bacteria for the first time to identify how alcohol might affect key brain proteins.
The discovery, by researchers at The University of Texas at Austin and the Pasteur Institute in France, paves way for eventually developing drugs that could disrupt the interaction between alcohol and the brain.
"Now that we've identified this key brain protein and understand its structure, it's possible to imagine developing a drug that could block the binding site," said Adron Harris, professor of biology and director of the Waggoner Center for Alcohol and Addiction at The University of Texas at Austin.

Harris and his former postdoctoral fellow Rebecca Howard, now an assistant professor at Skidmore College, are co-authors on the paper published in Nature Communications.
They described the structure of the brain protein, called a ligand-gated ion channel, that is a key enabler of many of the primary physiological and behavioural effects of alcohol.
Harris said that for some time there has been suggestive evidence that these ion channels are important binding sites for alcohol.

Researchers couldn't prove it, however, because they couldn't crystallise the brain protein well enough, and therefore couldn't use X-ray crystallography to determine the structure of the protein with and without alcohol present.

"For many of us in the alcohol field, this has been a Holy Grail, actually finding a binding site for alcohol on the brain proteins and showing it with X-ray crystallography," said Harris.
"But it hasn't been possible because it is not possible to get a nice crystal," Harris said.
The breakthrough came when Marc Delarue and his colleagues at the Pasteur Institute sequenced the genome of cyanobacteria Gloeobacter violaceus that grows only on rocks in the Swiss Alps.
They noted a protein sequence on the bacteria that is remarkably similar to the sequence of a group of ligand-gated ion channels in the human brain.

They were able to crystallise this protein.
Harris and Howard asked their French colleagues to collaborate, got the cyanobacteria, changed one amino acid to make it sensitive to alcohol, and then crystallised both the original bacteria and the mutated one.
They compared the two to see whether they could identify where the alcohol bound to the mutant.
"Everything validated that the cavity in which the alcohol bound is important. It doesn't account for all the things that alcohol does, but it appears to be important for a lot of them, including some of the 'rewarding' effects and some of the negative, aversive effects," Harris said.

Harris and his lab plan to use mice to observe how changes to the key protein affect behaviour when the mice consume alcohol.