RUB Scientists Investigating Molecular Switches: Publication in the Journal of Neuroscience
A: Cartoon of the normal operation of glutamate receptors. The three components of the joint which link the glutamate detection unit with the ion channel are marked in red.
B: Cartoon illustrating how changes of the joint components affect channel function. The channel will remain permanently open, whether there is any glutamate present or not.
An Important Hinged Joint
Glutamate receptors comprise a detection site for glutamate which is accurately dimensioned to take up the messenger transmitter, and a channel in the cell surface which can be opened and closed. As in a mouse trap, the detection site for glutamate will snap shut once the neurotransmitter has bound. This movement triggers the opening of the channel so positive charge carriers, which have accumulated outside, can flow into the cell where they generate an electric signal. The glutamate detection site and the channel are coupled to each other by means of a sophisticated three-part articulated mechanism. It is known of one of the three parts of the joint that even the smallest changes may result in major malfunctions. Mutations of this part of the joint in mice, for instance, affect the channel such that is permanently open, whether or not glutamate is available. Any normal signal transmission is then blocked, finally killing nerve cells.
Interaction Is What Counts
The exact structure of the joint and, in particular, the interaction of all three parts are largely unknown. These joints are moreover designed quite differently in the four types of glutamate receptors existing. In the present study the scientists have exchanged the individual parts of the joint among various glutamate receptors in order to better understand their basic functions and multiple options. They could actually determine that exactly those two parts of the joints which have been largely unknown so far will substantially impact receptor function. Changing one of these articulated components will cause the channels to remain permanently open, similar as in mouse mutations; changing the other will lead to total loss of channel function. If you combine the two modifications, you get a surprisingly normal function of the receptor again. "We think we have identified here two parts of the joint whose interaction is highly important. If they are sluggish, the channel cannot open any more; if they are easy-running, the channel will remain open all the time", Sabine Schmid concludes.
Requirements for Drug Development
To precisely define such mechanical principles in glutamate receptors is a precondition to understand abnormal changes of signal transmission and allow for purposeful intervention with medication. The three parts of the joint are especially interesting in this respect as they are very specific for the four different types of glutamate receptors; it will then be possible to develop drugs which address one single type of receptor only - an important condition to develop substances which will have no adverse side effects.
Background: Signal Transmission in the Brain
Our brain creates our imagination by switching electric signals within a huge network of approximately 100 billion nerve cells, the individual nerve cells not having direct electric contact to each other, but being separated by a very small gap. Any signals which are to be transmitted from one cell to the other need to bridge this gap. This is done by the so-called synapses, special points of contact, where signals are transmitted by way of a chemical messenger, the neurotransmitter, , which is discharged by the electrically excited nerve cell. The neurotransmitter then traverses the gap and is recognized by the recipient cell. In the brain, the most frequently used neurotransmitter will be the amino acid glutamate. Specialized molecular switches in the surface of the receiving cell, the so-called glutamate receptors, register the presence of glutamate in the gap, and translate this into an electric signal. The glutamate receptors play a highly important role in our brain; understanding their precise mechanics is indispensable if scientists wish to understand the way nerve cells are using them to encrypt messages.
Reference
Schmid SM, Körber C, Herrmann S, Werner M, Hollmann M.: "A domain linking the AMPA receptor agonist binding site to the ion pore controls gating and causes lurcher properties when mutated." In: Journal of Neuroscience 2007 Nov. 7; 27(45): 12230-12241.
Other Information
Prof. Dr. Michael Hollmann, Sabine Schmid, Biochemistry I - Receptor Biochemistry, Faculty of Chemistry and Biochemistry of the Ruhr-Universität, 44780 Bochum, Tel. +49 234/32-24225, Email: sabine.schmid@rub.de, michael.hollmann@rub.de
