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Discovery Of A Molecular Switch -- Progress In The Research On Anxiety

Date:
October 9, 2001
Source:
The Max Planck Society
Summary:
In the journal Proceedings of the National Academy of Sciences (September 25, 2001, Vol. 98) scientists of the Max Planck Institute of Experimental Medicine, Goettingen, report about their discovery of an amino acid-switch of the stress hormone corticotropin-releasing factor (CRF): by replacing a single amino acid, they were able to change selectively the binding properties of CRF. On the basis of this observation, the development of selective CRF-like agonists and antagonists should be facilitated.

In the journal Proceedings of the National Academy of Sciences (September 25, 2001, Vol. 98) scientists of the Max Planck Institute of Experimental Medicine, Goettingen, report about their discovery of an amino acid-switch of the stress hormone corticotropin-releasing factor (CRF): by replacing a single amino acid, they were able to change selectively the binding properties of CRF. On the basis of this observation, the development of selective CRF-like agonists and antagonists should be facilitated.

Everyone has experienced stressful situations associated with anxiety which can be triggered by numerous stimuli. Even though these stimuli may be very different - the chemical reactions triggered by them within the organism follow a basic pattern: in response to a stressful stimulus, humans as well as other mammals release from the hypothalamus, a defined brain region, a peptide called corticotropin-releasing factor, CRF, consisting of 41 amino acids. Hypothalamic CRF is secreted into the venous portal blood vessel system connecting the hypothalamus with the pituitary gland, and reaches the pituitary gland with the blood flow. There, it stimulates the release of another peptide hormone called corticotropin which is transported with the blood stream to the adrenal gland, where it stimulates the release of glucocorticoid hormones. Scientists refer to this signalling chain as hypothalamo-pituitary-adrenal axis or simply as stress axis. It plays an important role in the adaptation of the organism responding to stressful stimuli. Under pathological conditions, such as for example mood and anxiety disorders, the function of the stress axis may be strongly impaired.

Besides its role in the activation of the stress axis, CRF modulates several brain functions such as memory, anxiety and food intake. These actions of CRF in the brain are mediated by receptors, proteins anchored in cell membranes. These receptors bind CRF tightly and induce signal chains in the cells. Interestingly, CRF can enhance or weaken memory and anxiety in dependence of the receptor subtypes and brain regions involved. CRF is not only bound by receptors, but also by a binding protein. In the human brain, this binding protein binds approximately 50% of the endogenous CRF - actually more tightly than the CRF receptor. The biological role of the CRF binding protein is not well understood to date, however, it is clear that it represents a pharmacologically important reservoir of CRF that - for example - could be used to improve memory function.

The alpha-helical hydrophobic patch of amino acids 8, 12, 15, 19 and 22 of human/rat corticotropin-releasing factor (h/rCRF). h/rCRF binds to the CRF binding protein with an affinity which is three times higher than the affinity to CRF receptor subtype 1. Replacement of the amino acid 22, alanin (Ala), by the amino acid glutamic acid (Glu) lowers the affinity to the binding protein by a factor of 150 and increases the affinity to CRF receptor subtype 1 by a factor of 3.

For a better understanding of the brain functions mediated by CRF, scientists are interested in the development of CRF analogs selectively binding to the receptor or to the binding protein. In 1995, Andreas Ruehmann, Ines Bonk and Joachim Spiess of the Department of Molecular Neuroendocrinology of the Max Planck Institute of Experimental Medicine in Goettingen developed in collaboration with Chijen Lin and Michael Rosenfeld of the Howard Hughes Institute in San Diego the first CRF receptor subtype-specific antagonist, the peptide anti-sauvagine-30.

In this month's issue (No. 20) of the Proceedings of the National Academy of Sciences, scientists of the same Max Planck department, Klaus Eckart, Olaf Jahn, Jelena Radulovic, Hossein Tezval, Lars van Werven and Joachim Spiess report that a single amino acid is decisive for tight binding to the CRF binding protein: replacement of an alanine residue by a glutamic acid residue prevents binding to the binding protein, but not to the receptor. The "switch" residue is located in a hydrophobic patch of CRF (see figure).

Applying the new knowledge, the scientists succeeded already in chemical modification of a known antagonist by rendering it more soluble for in vivo experiments. The antagonist astressin becomes more acidic after incorporation of the "switch amino acid" glutamic acid. Furthermore, acidic astressin binds more tightly than astressin to either CRF receptor subtype, but does not bind anymore to the CRF binding protein. At the same time, the water solubility of acidic astressin was greatly increased so that it efficiently suppressed anxiety in animal experiments. Currently, the scientists of the Max Planck Institute in Goettingen work on the development of antagonists of even higher selectivity for CRF receptor subtypes.


Story Source:

The above story is based on materials provided by The Max Planck Society. Note: Materials may be edited for content and length.


Cite This Page:

The Max Planck Society. "Discovery Of A Molecular Switch -- Progress In The Research On Anxiety." ScienceDaily. ScienceDaily, 9 October 2001. <www.sciencedaily.com/releases/2001/10/011009070408.htm>.
The Max Planck Society. (2001, October 9). Discovery Of A Molecular Switch -- Progress In The Research On Anxiety. ScienceDaily. Retrieved July 24, 2014 from www.sciencedaily.com/releases/2001/10/011009070408.htm
The Max Planck Society. "Discovery Of A Molecular Switch -- Progress In The Research On Anxiety." ScienceDaily. www.sciencedaily.com/releases/2001/10/011009070408.htm (accessed July 24, 2014).

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