The title of this proposal for the NIH U01 is Identify functional modulators of ionotropic neurotransmitter receptors in brain. Dysregulation of neural circuits causes various types of neurological disorders including epilepsy, mental retardation, autism and ataxia. Neural circuits are constructed by neurons that communicate each other at synapses through neurotransmitters. Therefore, controlling synaptic transmission is crucial for human health. Neurotransmitters bind to and activate neurotransmitter receptors to transfer spike or to modulate synaptic transmission. Whereas genes encoding neurotransmitter receptors had been cloned last 25 years, recently several examples of functional modulators or auxiliary subunits of neurotransmitter receptors were identified. The existence of functional modulators burdens researchers with the cumbersome and time-consuming task of characterizing receptors by expressing receptor alone in heterologous cells. However, a critical barrier to the identification f functional modulators is technical concerns in traditional screening including proteomic approach and functional cloning approach. Therefore, we need to develop new methods for the identification of novel receptor modulators. In this proposal, using our novel high-throughput screening using transmembrane ORF collections, we will identify functional modulators of cationic ionotropic neurotransmitter receptors. Simultaneously, we will examine roles of modulators in receptor interaction, trafficking and channel properties. This unbiased, genome-wide, sensitive screening method will therefore have a deep impact in many research disciplines.
Receptor-ligand interaction mediates signaling within cells, between cells, and between cells and their environment. Defects in receptor-ligand interactions underlie many major disorders in humans, including developmental defects, metabolic disorders, and neurological disorders. Receptor-ligand interactions are one of best targets for drug development, and identification of receptor modulators allows us to identify novel targets for drug discovery in many disorders.
| Oprea, Tudor I; Bologa, Cristian G; Brunak, Søren et al. (2018) Unexplored therapeutic opportunities in the human genome. Nat Rev Drug Discov 17:317-332 |
| Yamasaki, Tokiwa; Hoyos-Ramirez, Erika; Martenson, James S et al. (2017) GARLH Family Proteins Stabilize GABAA Receptors at Synapses. Neuron 93:1138-1152.e6 |
| Martenson, James S; Yamasaki, Tokiwa; Chaudhury, Nashid H et al. (2017) Assembly rules for GABAA receptor complexes in the brain. Elife 6: |
