Receptor Believed Dead Comes To Life
Chimera discloses the secret of the black sheep of the glutamate receptor family
RUB researchers report their findings in PNAS
To all intents and purposes, the delta2 receptor is an unequivocal member of the family of glutamate receptors, the most important receptors for excitatory neurotransmitters in our brain. To date, however, this receptor has been considered the “black sheep” of the family because it does not react to glutamate, which, by definition, a glutamate receptor ought to do. This riddle fascinated the neuroscientists working with Prof. Michael Hollmann (Chair of Biochemistry I – Receptor Biochemistry) at the Ruhr University. To unlock the secret of this receptor, they “crossed” it with another glutamate receptor that functions normally. The resulting chimera is functional and opens an ion channel. The task now at hand is to identify a transmitter that triggers this mechanism in an unchanged, physiological delta2 receptor. The scientists have published their observations in the current edition of the Proceedings of the National Academy of Sciences, USA (PNAS).
Lively communication between brain cells
Our brain consists of a gigantic network of about 100 billion neurons. Every one of them is linked to other neurons by more than ten thousand contact sites. The universal language within this network consist of electrical impulses, the sum of which lead to the development of our world of thought in a hitherto completely unknown manner. The majority of contacts between neurons are not direct, as a few millionth of a cm separate the cells from one another. This distance must be overcome if a signal from a transmitting cell is to reach a receptor cell. This occurs at special contact sites, so-called synapses, which conduct incoming signals with the assistance of a chemical messenger, a so-called neurotransmitter. The activated transmitting cell discharges the messenger, which then crosses the synaptic cleft and is recognized by the receiving cell. This is where the glutamate receptors come into play. Protruding from the plasma membrane into the synaptic cleft they are specialized in registering the messenger most frequently found in the brain, namely glutamate – the well-known flavor enhancer in Chinese dishes, and subsequently convert the chemical signal into an electrical signal.
Conversion of chemical into electrical signals
Key to the secret of conversion of chemical into electrical signals is the structure of the receptors. They consist of three important parts: a glutamate recognition site, a joint, and a channel. The extracellular, bipartite recognition site protruding from the plasma membrane recognizes glutamate, binds it and then snaps shut like a mouse trap. Via a sophisticated joint mechanism, this closing movement is transmitted to the channel that traverses the cell membrane and causes the channel to open. Positive ions that have accumulated outside the cell can now flow into it and thereby generate an electrical signal.
Important but mysterious role
The delta2 receptor also has the three elements discussed above. Why then is it not activated by glutamate? Prof. Hollmann summarizes the problem by stating: "We know that the delta2 receptor is located at specific sites within the cerebellum, that it plays an extremely important role for the fine coordination of motor behaviour, and that it evidently contributes to the correct circuitry of the neurons during development of the cerebellum. What we don't know is just how the receptor fulfils these functions". The scientists thus decided to pursue the principal question whether the delta2 receptor is at all capable of functioning in a manner similar to that of the other glutamate receptors, namely as a neurotransmitter-activated ion channel.
Greek mythology helps
To answer this question the scientists recalled a very old idea: they produced a chimerical receptor. In Greek mythology, the chimera is a monstrous figure with a lion’s head, the body of a goat, and a snake's tail. Within the framework of her dissertation at the IGSN (International Graduate School of Neuroscience), Sabine Schmid created a chimeric delta2 receptor with the joint and channel of the delta2 receptor, but the ligand recognition site transplanted from a normally functioning relative. This chimeric receptor did indeed react to glutamate and opened its ion channel, which had previously been belived to be dead. Prof. Hollmann comments: "We thus have developed a tool that, for the first time, enables us to investigate of the unique properties of the joint and the ion channel of the delta2 receptor. Moreover, our results suggest that the secret of the delta2 receptor is to be found in the difference in its recognition site for neurotransmitters". To a certain degree, the scientists have thus managed to unveil the function of the “black sheep.” The next step is to determine to which signal the actual recognition site of the delta2 receptor reacts and which role this plays for its essential function in the cerebellum.
Schmid SM, Kott S, Sager C, Hülsken T, Hollmann M: “The glutamate receptor subunit delta2 is capable of gating its intrinsic ion channel as revealed by ligand binding domain transplantation” In: Proceedings of the National Academy of Sciences; doi:10.1073/pnas.0900329106
of the exchange of the delta2 receptor's intrinsic ligand recognition site (red). The recognition site from another glutamate receptor (blue) enables conversion of chemical into electrical signals: the reputedly dead ion channel springs to life!