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When the stress brake fails

First discovered ten years ago, it is now the subject of new findings relating to its function: the protein SPRED2 inhibits the hormonal stress response in the body. Whether it also plays a role in the development of illnesses has yet to be established.

SPRED2: This protein is found in humans and other mammals. Among those who discovered it is a team of scientists from the University of Würzburg led by Kai Schuh. The professor is researching the function that this protein performs. In this area, he and his doctoral student Melanie Ullrich as well as other colleagues from Würzburg, Ulm, and Stockholm have now made new findings that are reported in the Journal of Biological Chemistry.

Insights into the function of the protein were gained by the scientists using mice that lack the SPRED2 gene and are therefore unable to create the protein. These animals demonstrate unusual behavior: they drink twice as much as normal mice and scratch themselves extremely often, such as behind the ears.

Abnormal hormonal states

Why this abnormal behavior? To clarify this, the researchers from the University of Würzburg's Institute of Physiology analyzed the organism of these animals very closely. One of the discoveries they made were significantly elevated quantities of the stress hormone cortisone and of the hormone aldosterone. The latter causes an increase in the concentration of salt in the blood, thereby raising blood pressure. Consequently, the mice drink more water so they can expel the excess salt more successfully.

The studies revealed other striking irregularities. The synapses in the brain release a greater number of transmitters. There is also an overabundance of the hormones CRH and ACTH, which are formed in the brain and the pituitary gland: these two transmitters in a signal chain control the production of the hormones cortisone and aldosterone in the adrenal cortex.

SPRED2, an inhibitor protein

The researchers concluded that if the organism is missing the protein SPRED2 the hormonal signal chain from the brain to the pituitary gland to the adrenal cortex is activated far too strongly. It would appear that the protein has the effect of slowing down this system that the organism sets in motion whenever it has to overcome physical or mental stress.

This therefore means that, hormonally speaking, SPRED2-free mice are in a state of permanent stress. The researchers are therefore interpreting the continuous scratching that they observe with these animals as a stress-related compulsion. "The elevated quantity of cortisone simulates stress for them," says Kai Schuh. No evidence has been found of other conceivable causes for the scratching, such as diabetes.

Illnesses due to defective SPRED2?

The absence of SPRED2 leads to a hormone surplus with too much cortisone and aldosterone - this would suggest that a malfunction of this gene could have something to do with high blood pressure or other illnesses, such as depression. Scientists are also considering genetic causes for both ailments.

"We are not currently aware of any illnesses in humans that are connected to SPRED2," says Professor Schuh. But this could all change, as the example of the closely related SPRED1 gene shows: geneticists only recently proved for the first time that a defect to this gene is the sole cause of neurofibromatosis, tumor-like growths of the nerve tissue.

Next steps for the researchers

There are many questions relating to the function of the SPRED2 protein that the Würzburg researchers have yet to answer. They want to work with neurophysiologists to analyze why the synapses in the brain are overactive without the protein. They are also looking in nerve cells for molecules that interact with SPRED2.

Are the mice really scratching because the hormones are simulating a stress situation for them? Behavioral experiments, conducted in collaboration with Professor Klaus-Peter Lesch from the Department of Psychiatry, should answer this question. The scientists are also planning to administer a common antidepressant to the "stressed" animals as an experiment to see whether it might alleviate the symptoms at all.

Identification of Sprouty-related protein with EVH-1 domain (SPRED) 2 as a negative regulator of the Hypothalamic-Pituitary-Adrenal (HPA) axis, Melanie Ullrich, Karin Bundschu, Peter M. Benz, Marco Abesser, Ruth Freudinger, Tobias Fischer, Julia Ullrich, Thomas Renne, Ulrich Walter, and Kai Schuh, The Journal of Biological Chemistry, Vol. 286, Issue 11, 9477-9488, March 18, 2011, DOI 10.1074/jbc.M110.171306

Contact

Prof. Dr. Kai Schuh, Institute of Physiology at the University of Würzburg, T +49 (0)931 31-82740, kai.schuh@uni-wuerzburg.de

idw :: 21.03.2011