Researchers decipher assembly of glutamate receptors and its importance for memory formation
Rapid communication of neurons in the brain, as well as the ability to learn, fundamentally rely on neurotransmitter receptors located in the contact sites of neurons, the synapses.
The most important receptors in the mammalian brain are glutamate receptors of the AMPA-type (AMPAR) that generate the electrical signal required for fast communication between neurons. The number of AMPARs is modulated by the degree of a synapse’s activity:
As it learns, the number of AMPARs increases, thus making synaptic signal transduction more reliable and driving synaptic plasticity that promotes memory formation. Fundamental requirement for this synaptic plasticity is the efficient assembly of AMPARs from different protein subunits in the endoplasmic reticulum (ER) of nerve cells, for which little or no information has been avaible so far.
For the first time, a team of neurobiologists from Freiburg headed by Prof. Dr. Bernd Fakler from the Institute of Physiology, in cooperation with colleagues from the Goethe University Frankfurt and the Max Planck Institute for Medical Research in Heidelberg, has been able to show that AMPARs are assembled from main and auxiliary subunits in a step-by-step process much like on an assembly line.
The individual stages are carried out by different ER-resident proteins and protein complexes. Disturbance of this assembly by mutations in the assembly line elements in humans or by their targeted genetic inactivation - knock-out - in mice, leads to massive impairment of synaptic signal transduction and learning.
Conversely, the increase in receptor production through overexpression of the assembly line proteins leads to increased plasticity of the synapses. The scientists recently published these results in the journal Neuron.
Using high-resolution proteomic techniques, the researchers have identified proteins in the ER membranes of neurons that are required for the assembly of functional AMPARs from four pore-forming subunits and four auxiliary subunits: The first building block, the proteins ABHD6 and PORCN, protects the individual pore-forming GluA subunits from premature degradation.
The second building block, a complex of the proteins FRRS1l and CPT1c, assembles four GluA-protein into a receptor channel and prepares their association with the four auxiliary subunits, the cornichon or TARP proteins. This final step dissociates the FRRS1l-CPT1c complex and enables export of the functional AMPARs from the ER and their transport into the synapses.
The individual steps along this assembly line are precisely orchestrated and optimized for the efficient assembly of the receptors.
If the operation of the assembly line is disturbed, for example by mutation-related loss of function of the FRRS1l protein, this leads to severe dysfunction of the brain in humans, as described by the researchers in an earlier work in 2017:
All patients showed severely restricted intellectual abilities with IQ-values below 40, delayed or missing speech development and an increased tendency for epileptic seizures.
Although the newly identified assembly line is specific for AMPARs, the researchers assume that the process of stepwise assembly is exemplary for other membrane proteins and protein complexes mediating information processing in the brain, propagation of excitation and/or substrate transport in other types of cells.
The scientists Drs. Jochen Schwenk, Sami Boudkkazi, Maciej Kocylowski and Bernd Fakler work at the Institute of Physiology. Fakler is a member of the Clusters of Excellence in biological signalling research CIBSS and BIOSS at the University of Freiburg.
Schwenk, S. Boudkkazi, M. Kocylowski, A. Brechet, G. Zolles, T. Bus, K. Costa, W. Bildl, A. Kollewe, J. Jordan, J. Bank, W. Bildl, R. Sprengel, A. Kulik, J. Roeper, U. Schulte, and B. Fakler (2019): An ER assembly line of AMPA-receptors controls excitatory neurotransmission and its plasticity. In: Neuron. DOI: https://doi.org/10.1016/j.neuron.2019.08.033
Prof. Dr. Bernd Fakler
Institute of Physiology, Department II
Clsuters of Excellence in biological signalling studies CIBSS and BIOSS
University of Freiburg
Nicolas Scherger | idw - Informationsdienst Wissenschaft
Human skin is an important source of ammonia emissions
27.05.2020 | Max-Planck-Institut für Chemie
Biotechnology: Triggered by light, a novel way to switch on an enzyme
27.05.2020 | Westfälische Wilhelms-Universität Münster
In living cells, enzymes drive biochemical metabolic processes enabling reactions to take place efficiently. It is this very ability which allows them to be used as catalysts in biotechnology, for example to create chemical products such as pharmaceutics. Researchers now identified an enzyme that, when illuminated with blue light, becomes catalytically active and initiates a reaction that was previously unknown in enzymatics. The study was published in "Nature Communications".
Enzymes: they are the central drivers for biochemical metabolic processes in every living cell, enabling reactions to take place efficiently. It is this very...
Early detection of tumors is extremely important in treating cancer. A new technique developed by researchers at the University of California, Davis offers a significant advance in using magnetic resonance imaging to pick out even very small tumors from normal tissue. The work is published May 25 in the journal Nature Nanotechnology.
researchers at the University of California, Davis offers a significant advance in using magnetic resonance imaging to pick out even very small tumors from...
Microelectronics as a key technology enables numerous innovations in the field of intelligent medical technology. The Fraunhofer Institute for Biomedical Engineering IBMT coordinates the BMBF cooperative project "I-call" realizing the first electronic system for ultrasound-based, safe and interference-resistant data transmission between implants in the human body.
When microelectronic systems are used for medical applications, they have to meet high requirements in terms of biocompatibility, reliability, energy...
Thomas Heine, Professor of Theoretical Chemistry at TU Dresden, together with his team, first predicted a topological 2D polymer in 2019. Only one year later, an international team led by Italian researchers was able to synthesize these materials and experimentally prove their topological properties. For the renowned journal Nature Materials, this was the occasion to invite Thomas Heine to a News and Views article, which was published this week. Under the title "Making 2D Topological Polymers a reality" Prof. Heine describes how his theory became a reality.
Ultrathin materials are extremely interesting as building blocks for next generation nano electronic devices, as it is much easier to make circuits and other...
Scientists took a leukocyte as the blueprint and developed a microrobot that has the size, shape and moving capabilities of a white blood cell. Simulating a blood vessel in a laboratory setting, they succeeded in magnetically navigating the ball-shaped microroller through this dynamic and dense environment. The drug-delivery vehicle withstood the simulated blood flow, pushing the developments in targeted drug delivery a step further: inside the body, there is no better access route to all tissues and organs than the circulatory system. A robot that could actually travel through this finely woven web would revolutionize the minimally-invasive treatment of illnesses.
A team of scientists from the Max Planck Institute for Intelligent Systems (MPI-IS) in Stuttgart invented a tiny microrobot that resembles a white blood cell...
19.05.2020 | Event News
07.04.2020 | Event News
06.04.2020 | Event News
28.05.2020 | Transportation and Logistics
28.05.2020 | Physics and Astronomy
28.05.2020 | Power and Electrical Engineering