Researchers observe at the atomic level the neuronal ‘gate’ for essential molecules in learning and memory
A new study, published in Nature Communications, unveils its structure and mechanism of action of the Asc-1 protein, which serves as the gateway, opening and closing, for fundamental amino acids involved in cognitive processes. the work is a collaboration between the Institute for Research in Biomedicine (IRB Barcelona), based in PCB, the Spanish National Cancer Research Center (CNIO), the Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), and the University of Barcelona. The finding could facilitate the design of drugs to treat schizophrenia, ictus, and other neurological diseases.
Learning from an experience, remembering a story, changing an attitude… all our behaviour stems from the exchange of chemical compounds between neurons—the neurotransmitters. Unravelling what exactly happens at the molecular level when neurons talk to each other, at the synapses, is crucial for understanding the human brain as a whole, which is particularly key for addressing mental health problems.
Now, the authors of a colaborative study from IRB Barcelona, the University of Barcelona, CNIO and CIBERER have observed and described the structure of a protein in the membrane of neurons that acts like a gate, opening and closing. In this regard, protein Asc1/CD98hc (Asc1 in its abbreviated form) is a specific transporter for certain amino acids that are crucial for learning and memory.
The activity of the protein Asc-1 has been associated with various kinds of mental illness, and unravelling its 3D structure will facilitate the development of new drugs for these conditions.
“The collaboration between IRB Barcelona, CNIO and UB has played a pivotal role in unravelling the mysteries of Asc-1, offering us an unprecedented understanding of its structure and function. This breakthrough not only sheds light on the complex cellular machinery underlying fundamental cognitive processes but also brings us closer to the development of more precise therapeutic interventions for a range of neurological disorders,” adds Dr. Manuel Palacín, head of the Amino Acid Transporters and Disease laboratory at IRB Barcelona and Professor in the Department of Biochemistry and Molecular Biomedicine at the Faculty of Biology of the UB.
Together with Dr. Manuel Palacín, Dr. Óscar Llorca from CNIO and Dr. Ekaitz Errasti-Murugarren, from the University of Barcelona and CIBERER, are also co-authors of this study. The first authors are Josep Rullo-Tubau (IRB Barcelona) and Dr. María Martínez Molledo (CNIO).
Implications for neurological diseases
All cells in the body have gates on their membranes through which to exchange substances with the external environment: proteins that constantly open and close in response to the cell’s needs. These gates can either open inwards to take in molecules like amino acids, or outwards, through a shape alteration, to release them, or vice versa.
The protein Asc-1 is found mainly in the neurons of the hippocampus and cerebral cortex in the brain. It specialises in introducing and/or removing two amino acids that are key for neuronal connections (synapses), which are involved in learning, memory, and brain plasticity—the nervous system’s ability to adapt its circuits in response to new stimuli.
Changes in the availability of these amino acids, known as D-serine and glycine, have been linked to conditions such as schizophrenia, stroke, ALS, and other neurological disorders. Efforts have long been underway to develop drugs that can regulate the activity of Asc-1 to address these diseases, but all without success so far. Detailed knowledge of the atomic structure of Asc-1 provides crucial information to achieve this goal.
» For further information: IRB Barcelona website [+]
» Reference article: Josep Rullo-Tubau, Maria Martinez-Molledo, Paola Bartoccioni, Ignasi Puch-Giner, Ángela Arias, Suwipa Saen-Oon, Camille Stephan-Otto Attolini, Rafael Artuch, Lucía Díaz, Víctor Guallar, Ekaitz Errasti-Murugarren, Manuel Palacín & Oscar Llorca. “Structure and mechanisms of transport of human Asc1/CD98hc amino acid transporter”. Nature Communications 15, 2986 (2024). DOI: 10.1038/s41467-024-47385-3