Crystallization Aids Study of Neuron Receptors

Researchers using protein crystallization techniques have found that perturbations at the molecular structure level govern desensitization of neurons and reduced response to neurotransmitters. This work, which helps to explain how experimental, memory-enhancing drugs affect the brain on a molecular level, was published in the May 16, 2002, issue of Nature.

"Learning how neurons respond to neurotransmitters is important not only to understanding basic brain functioning, but also may one day lead to new insights into a variety of new therapies,” said Duane Alexander, Director of the National Institute of Child Health and Human Development (Bethesda MD, USA), which conducted the research.

The GLUR2 AMPA-sensitive glutamate receptor, one of the ligand-gated ion channels, was the subject of the study. Investigators took advantage of the fact that after activation many ligand-gated ion channels enter a desensitized state in which the neurotransmitter remains bound but the ion channel is closed. One part of the glutamate receptor was isolated by biochemical methods, and its structure was examined at the atomic level. Researchers then designed altered receptors and determined their atomic structures as well. By observing how experimental drugs interacted with both mutant and normal receptors, they hoped to gain more insights into how the drugs interact with the receptor and into the process of desensitization.

Results showed that receptor activation involves conformational changes within each receptor subunit that produce an increase in the separation of portions of the receptor that are linked to the ion channel. Desensitization occurs through rearrangements that dislocate the ligand-binding core from the ion channel gate.



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