Final Report Summary - MOAMAUX (Modulation of AMPA receptor properties by auxiliary subunits.)
The main aim of Dr. David Soto's research group is to better understand different aspects of the AMPARs function.
AMPARs mediate most of fast excitatory synaptic transmission in the central nervous system and they are essential for some types of plasticity. Furthermore, they are also involved in pathological conditions. AMPAR properties differ depending on their subunit composition and also depending on accessory subunits. These auxiliary transmembrane proteins are important in controlling both the trafficking and the gating of the AMPARs.
The research performed in the last two decades has clarify that AMPAR trafficking is a key regulatory mechanism in controlling processes like synaptic plasticity (and thus learning and memory). Unraveling the complexity of these trafficking pathways and the exact role of the different players it is crucial to understand the role of AMPAR on higher brain function. In this context, David Soto´s group has shed light on the role of two of these proteins (stargazin and CPT1C) that interact with AMPAR complexes and that are able to regulate AMPAR function by controlling their behavior and their traffic to the plasma membrane.
They have investigated how stargazin (the prototypical auxiliary subunit of AMPARs) modulates channel function by modifying the influence of key residues of the receptor and unravelling the mechanisms and parts of the stargazin responsible of the effect of this auxiliary subunit on key properties of CP-AMPARs: single channel conductance and intracellular block by polyamines. Their work has been published in the prestigious Journal of Neuroscience.
They have also discovered a new functional partner of AMPARs: carnitine palmitoyltransferase 1C (CPT1C). They have studied the effect of CPT1C (an atypical member of CPT1 family of enzymes expressed in the endoplasmic reticulum of neurons and which function remained unknown) on AMPAR subunits. Their research work found that CPT1C can interact with several GluA subunits but it only exert its effect on GluA1-containing AMPARs, which consists in increasing the surface expression of GluA1 subunit. They did deepen also in the molecular mechanisms of such trafficking modulation by discovering that the effect of CPT1C on GluA1 subunits relies on a specific cysteine residue of GluA1 (585). They have also confirmed the important role of CPT1C on AMPAR trafficking by electrophysiological recordings in CPT1C knockout animals. These results have been published in Frontiers in Cellular Neuroscience and The Journal of Biological Chemistry.
After the “Career Integration Grant” finalization, they are continuing the work on the exact molecular mechanism involved CPT1C modulation of AMPARs (chaperone effect, palmitoylation state of the receptor) and the Group has promising results that will be sent soon for publication.
In the recent years, the work carried out by international research groups in the AMPAR field studying proteins interacting with AMPAR has been very important. A large number of publications in high impact factor journals during the last years reveal the importance of proteins involved in biogenesis, trafficking and channel modulation of AMPARs. In this background, David Soto laboratory is contributing in the state-of-the-art of this important class of receptors from the brain and providing knowledge on their new interacting proteins.
The results obtained with this research have been a key element for the implantation of a new research line in the group of the principal investigator and the funding awarded by the European Commission (Marie Curie CIG of the Seventh Framework Programme) has been proved fundamental for the achievement of the proposed objectives and the correct functioning of the laboratory. The re-integration of the principal investigator will finally be in an institution other than IDIBELL due to the possibility of holding an Associate position at the University of Barcelona. The awarding of new funding from the Spanish ministry for two more years to follow up with this new research line will be a key determinant for the future of this new research group.
AMPARs mediate most of fast excitatory synaptic transmission in the central nervous system and they are essential for some types of plasticity. Furthermore, they are also involved in pathological conditions. AMPAR properties differ depending on their subunit composition and also depending on accessory subunits. These auxiliary transmembrane proteins are important in controlling both the trafficking and the gating of the AMPARs.
The research performed in the last two decades has clarify that AMPAR trafficking is a key regulatory mechanism in controlling processes like synaptic plasticity (and thus learning and memory). Unraveling the complexity of these trafficking pathways and the exact role of the different players it is crucial to understand the role of AMPAR on higher brain function. In this context, David Soto´s group has shed light on the role of two of these proteins (stargazin and CPT1C) that interact with AMPAR complexes and that are able to regulate AMPAR function by controlling their behavior and their traffic to the plasma membrane.
They have investigated how stargazin (the prototypical auxiliary subunit of AMPARs) modulates channel function by modifying the influence of key residues of the receptor and unravelling the mechanisms and parts of the stargazin responsible of the effect of this auxiliary subunit on key properties of CP-AMPARs: single channel conductance and intracellular block by polyamines. Their work has been published in the prestigious Journal of Neuroscience.
They have also discovered a new functional partner of AMPARs: carnitine palmitoyltransferase 1C (CPT1C). They have studied the effect of CPT1C (an atypical member of CPT1 family of enzymes expressed in the endoplasmic reticulum of neurons and which function remained unknown) on AMPAR subunits. Their research work found that CPT1C can interact with several GluA subunits but it only exert its effect on GluA1-containing AMPARs, which consists in increasing the surface expression of GluA1 subunit. They did deepen also in the molecular mechanisms of such trafficking modulation by discovering that the effect of CPT1C on GluA1 subunits relies on a specific cysteine residue of GluA1 (585). They have also confirmed the important role of CPT1C on AMPAR trafficking by electrophysiological recordings in CPT1C knockout animals. These results have been published in Frontiers in Cellular Neuroscience and The Journal of Biological Chemistry.
After the “Career Integration Grant” finalization, they are continuing the work on the exact molecular mechanism involved CPT1C modulation of AMPARs (chaperone effect, palmitoylation state of the receptor) and the Group has promising results that will be sent soon for publication.
In the recent years, the work carried out by international research groups in the AMPAR field studying proteins interacting with AMPAR has been very important. A large number of publications in high impact factor journals during the last years reveal the importance of proteins involved in biogenesis, trafficking and channel modulation of AMPARs. In this background, David Soto laboratory is contributing in the state-of-the-art of this important class of receptors from the brain and providing knowledge on their new interacting proteins.
The results obtained with this research have been a key element for the implantation of a new research line in the group of the principal investigator and the funding awarded by the European Commission (Marie Curie CIG of the Seventh Framework Programme) has been proved fundamental for the achievement of the proposed objectives and the correct functioning of the laboratory. The re-integration of the principal investigator will finally be in an institution other than IDIBELL due to the possibility of holding an Associate position at the University of Barcelona. The awarding of new funding from the Spanish ministry for two more years to follow up with this new research line will be a key determinant for the future of this new research group.