Structural determinants of glutamate receptor regulation by auxiliary membrane anchored proteins

NSF Number: 1818213 BSF Number: 2017759 Abstract in Layman’s Terms Title: NSF/MCB-BSF: Collaborative Research: Towards development of the structural determinants of the Glutamate receptor gating regulation by auxiliary membrane anchored proteins

Principal investigators: Prof. Yael Stern-Bach, Hebrew University, Jerusalem, Israel; Prof. Maria Kurnikova, Carnegie Mellon University, Pittsburgh, PA USA; Prof. Alexander Sobolevsky, Columbia University Medical Center, New York, NY USA.

The vast cell-to-cell communication in the nervous system is mediated by small chemicals (called neurotransmitters) that are released from one cell and bind to receptor proteins present on the membrane of the adjacent cell, and fall into two types: inhibitory and excitatory. The amino-acid glutamate and its conjugate glutamate receptors are responsible for the majority of the excitatory neurotransmission in the mammalian brain. In addition, these glutamate receptors play critical roles in development and higher order cognitive function including learning and memory. Defects in glutamate receptor neurotransmission are implicated in a number of brain pathologies such as ischemia, epilepsy Alzheimer's disease, and schizophrenia to name a few. Glutamate receptors are protein complexes of four subunits that assemble in various combinations, creating membrane-embedded ion-channels of different types and properties. The role of glutamate receptors in brain plasticity depends on receptor composition, distribution and density in specific neuronal cell domains. A number of neurodegenerative diseases have been associated with a specific defect in either the assembly or function of glutamate receptor complexes. Recent studies, including independent work from our groups, showed that glutamate receptors interact with other proteins that regulate receptor properties at multiple levels and in opposing directions. Therefore, elucidating the structure and function of glutamate receptors, in general, and how these receptors are regulated by association with accessory proteins, in particular, is central to understanding brain physiology in health and disease. Here we propose to concentrate on the interaction of the AMPA-type glutamate receptors with the newly discovered CKAMP family of auxiliary proteins and their interplay with the well-known auxiliary proteins of the TARP family. These mechanisms are key steps at which AMPA receptors are regulated in synaptic transmission and plasticity. Thus, in addition to providing fundamental insights into AMPA receptor function, the results of this study will serve as a roadmap for investigations of AMPA receptor mediated processes in synaptic physiology. Moreover, these auxiliary proteins might also represent novel therapeutic targets to treat various neurological and psychiatric disorders known to be due to defects in AMPA receptor function.