May 16, 2002 Researchers at the National Institute of Child Health and Human Development (NICHD) and the Howard Hughes Medical Institute have come one step closer to understanding how experimental, memory-enhancing drugs affect the brain on a molecular level. The researchers published their results in the May 16 issue of Nature.
The finding provides an important insight into the mechanisms that regulate the sensitivity of brain cells to neurotransmitters, the chemical messengers that the cells use to communicate with one another.
"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, Director of the NICHD.
Like a key fits into a lock, neurotransmitters fit into specific sites, or receptors, studding the surface of brain cells. In an elaborate relay system, a cell that is excited by one neurotransmitter will, in turn, release neurotransmitters of its own. These affect still other cells, which, in turn, release more neurotransmitters, and so on. In this way, messages are transmitted throughout the brain's various mental circuits.
The researchers studied one of the glutamate receptors, found throughout the brain and involved in numerous learning and memory processes. Whether in the brain or in laboratory cultures, many receptors show reduced activity when exposed to higher-than-normal amounts of a neurotransmitter, a process called desensitization. Essentially, the cells become less sensitive to the effects of neurotransmitters.
According to an NICHD author of the paper, Mark Mayer, head of the Laboratory of Cellular and Molecular Neurophysiology, the researchers biochemically isolated one part of the glutamate receptor and determined its structure at the atomic level. They then designed altered, or mutant, receptors and determined their atomic structures as well. By observing how the drugs interacted with both mutant and normal receptors, the researchers could gain more insight into how the drugs interact with the receptor, and into the process of desensitization.
They found that experimental drugs, known as allosteric modulators, regulate desensitization by binding to a second site on the receptor separate from the binding site for glutamate itself. Receptors that had chemically bonded with allosteric modulators were more likely to also bond with glutamate molecules. The researchers hope that future efforts to understand the molecular action of additional classes of allosteric modulators may lead to novel insights into both the receptors themselves and the design of potential new treatments for disorders such as Alzheimer's disease.
The NICHD is part of the National Institutes of Health, the biomedical research arm of the federal government. The Institute sponsors research on development, before and after birth; maternal, child, and family health; reproductive biology and population issues; and medical rehabilitation. NICHD publications, as well as information about the Institute, are available from the NICHD Web site, http://www.nichd.nih.gov, or from the NICHD Clearinghouse, 1-800-370-2943; e-mail NICHDClearinghouse@mail.nih.gov.
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