(NIDDK) and the National Institute on Deafness and Other Communication Disorders (NIDCD), two of the National Institutes of Health (NIH). The improved performance is related to how closely couple the chemical and receptor are, the scientists conclude, with a loose connection being more effective than a tight one. The findings are at odds with the widely held notion that the stronger the association between a hormone and its receptor, the more effective its cellular signaling. If the findings hold true for similar hormone-receptor reactions, they could help change the way that drug therapies are designed for a host of health problems, from smell and taste disorders to heart disease, asthma, migraine, and pain. The study is published in the May 12, 2006, issue of the "Journal of Biological Chemistry".
The researchers looked at thyrotropin-releasing hormone, or TRH, a hormone released in the brain that kicks off a chain of events throughout the body, including the stimulation of the thyroid gland. As with many of the body's hormones, cells recognize TRH using a receptor belonging to a mega-family of proteins known as G-protein-coupled receptors (GPCRs), which play a lead role in cell-to-cell communication. When a hormone binds to its designated GPCR on the outside of a cell, a specific G-protein is activated within the cell, initiating a cascade of biochemical events leading to the unique and appropriate cellular response to that hormone.
"GPCRs are the targets of roughly a third of medicines sold today, so if this finding for TRH holds for other GPCR targets, it could have significant implications for drug development," says Marvin C. Gershengorn, M.D., director of NIDDK's Di vision of Intramural Research and senior author of the paper.
"At first glance, a cellular process that affects the thyroid gland may not seem especially meaningful to the study of communication disorders," says John Northup, Ph.D., who heads the Section on Signal Transduction of NIDCD's Laboratory of Cellular Biology. "However this research provides information that is fundamental to cellular signaling, a function that is essential to all cells in all systems in the body, including our sensory systems of hearing, balance, taste, and smell."
By tweaking portions of the TRH molecule, the researchers developed six slightly edited versions, while retaining most of the properties of the natural hormone. Measuring the cellular response when hormone meets receptor, they found that the lower the affinity between the two, the stronger the signal that is elicited, with certain analogs performing up to twice as effectively as TRH. As to why this would be the case, the researchers suggest that a loose connection between hormone and GPCR may allow a hormone to repetitively dock to and undock from its associated GPCR, activating a succession of G-proteins, and firing signal after signal. A tight connection, alternatively, may tie up a hormone with its GPCR, activating one G-protein, and limiting its signaling ability.
In future studies, the scientists hope to determine whether their findings are consistent with other hormone-GPCR reactions. Other researchers taking part in the study represent the National Institute of Pharmaceutical Education and Research, Punjab, India.