If the stress brake fails
It was discovered a decade ago, now there are new insights into its function: The protein in the body slows SPRED2 the hormonal stress response. Whether in the development of diseases, it plays a role, it is not clear yet.
SPRED2: This protein is found in humans and other mammals. Its discoverers include scientists from the University of Würzburg from Kai Schuh's working group. The professor investigates which function the protein fulfills. Together with his doctoral student Melanie Ullrich and other colleagues from Würzburg, Ulm and Stockholm, he has now gained new insights in this area, which the Journal of Biological Chemistry reports on.
The scientists gained insight into the function of the protein with mice that lack the SPRED2 gene and are therefore unable to produce the protein. The animals show an unusual behavior: they drink twice as much as normal mice and scratch themselves extremely often, for example behind the ears.
Abnormal hormonal conditions
Why this abnormal behavior? In order to clarify this, the researchers from the Physiological Institute of the University of Würzburg analyzed the organism of the animals very precisely. Among other things, they found significantly increased amounts of the stress hormone cortisone and the hormone aldosterone. The latter increases the salt concentration in the blood and thus the blood pressure. Consequence: The mice drink more water to be able to excrete the excess salt better.
The investigations revealed further abnormalities. The synapses in the brain increasingly release messenger substances. The hormones CRH and ACTH, which are formed in the brain and in the pituitary gland, are also far too abundant: the two messenger substances regulate the production of the hormones cortisone and aldosterone in the adrenal cortex in a signal chain.
SPRED2, a braking protein
Conclusion of the researchers: If the protein SPRED2 is missing in the organism, the hormonal signal chain brain-pituitary gland-adrenal cortex is far too strongly activated. Apparently, the protein exerts a braking effect on this system, which the organism always activates when it has to cope with physical or psychological stress.
The SPRED2-free mice are hormonally adjusted to permanent stress. That is why the researchers interpret the constant scratching that they observe in the animals as a stress-related compulsion. "The increased amount of cortisone gives them the illusion of stress," says Kai Schuh. Other conceivable causes of the scratching, such as diabetes, could not be proven.
Diseases caused by defective SPRED2?
Without SPRED2, an excess of hormones occurs with too much cortisone and aldosterone - so the idea arises that a malfunction of this gene could have something to do with high blood pressure or other diseases such as depression. Scientists are also considering genetic causes for both conditions.
"We still don't know of any disease in humans that is associated with SPRED2," says Professor Schuh. But that can change, as the example of the closely related SPRED1 gene shows: only recently did geneticists prove for the first time that a defect in this gene is the sole cause of neurofibromatosis, tumor-like growths in nerve tissue.
Researchers' next steps
The Würzburg researchers still have to answer many questions about the function of the SPRED2 protein. Together with neurophysiologists, they want to analyze why the synapses in the brain are overly active without the protein. They also look for molecules in the nerve cells that interact with SPRED2.
Are the mice actually scratching themselves because the hormones are simulating a stressful situation? Behavioral experiments, carried out in cooperation with Professor Klaus-Peter Lesch from the Psychiatric Clinic, are intended to answer this question. The scientists also want to test the "stressed" animals with a common antidepressant - to see whether it can alleviate the symptoms.
"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
Source: Munich [LMU]
