"Learning how neurons respond to neurotransmitters is important not only to understanding basic brain functioning, but also may one day lead to new insight into a variety of new therapies," said Duane Alexander of the National Institutes of Health (USA).

The researchers studied a glutamate receptor termed the GluR2 AMPA-sensitive glutamate receptor, which is found throughout the brain and is involved in numerous learning and memory processes. In both in vitro and in vivo work, a large proportion of these receptors demonstrate reduced activity when exposed to higher-than-normal levels of glutamate, an example of the general process called desensitization.

According to coauthor Mark Mayer, the researchers biochemically isolated one part of the glutamate receptor and determined its atomic structure. They then designed modified receptors and determined their atomic structures, as well. In the observation of how the drugs interacted with both normal and modified receptors, the researchers gained insight into how the drugs interact with the receptor to affect the process of desensitization.

The researchers found that the experimental drugs known as allosteric modulators regulate desensitization by binding to a second site on the receptor, a site different from the binding site for glutamate itself. Receptors that had bonded chemically with allosteric modulators were more likely to also bond with glutamate molecules. Thus, the effect of the allosteric modulator (the drug) was to make the receptors functionally more sensitive to glutamate, the natural neurotransmitter.

The researchers hope that future efforts to understand the molecular action of additional classes of allosteric modulators may lead to novel insights into the receptors themselves and enable investigators to design potential new treatments for disorders such as Alzheimer's disease.