University of Copenhagen
Towards Cognition Enhancing Therapeutics: Regiospecific Modulation of GABAB Receptors using Peptide-Based Inhibitors
SESSION 3: NOVEL MODULATORS OF BIOLOGY
Sunday, June 25, 2023, at 03:05 pm - 03:25 pm
Neuronal function is dependent on tightly regulated processes and a fine-tuned balance of synaptic excitation and inhibition. γ-Amino butyric acid, GABA, is the primary inhibitory neurotransmitter in the central nervous system, CNS, and activates ionotropic GABAA and metabotropic GABAB receptors, GBRs, to modulate neuronal inhibition. The GBR is recognized as a major component in learning and memory, and dysfunction has been implicated in severe neurological disorders such as depression, anxiety, schizophrenia, and cognitive deficits.
Recent proteomic studies identified three transmembrane proteins interacting specifically with the GB1a/2 receptor through the sushi domains, SDs: the amyloid precursor protein, APP, the adherence-junction associated protein 1, AJAP1, and the PILRa-associated neural protein, PIANP.
Functionally, APP mediates the trafficking of GB1a/2 receptors to the presynaptic site, where GB1a/2 receptors are likely transferred to AJAP1 or PIANP that localize the receptor at the cell surface. Activated presynaptic GBRs at glutamatergic terminals inhibit the release of neurotransmitters and thereby inhibit excitatory neuronal transmission.
In this study, we aim to specifically target presynaptic GBRs, as a novel principle for a regulated increase in glutamate release and thereby providing novel means to potentially treat diseases related to cognitive impairment. We first employed a microarray peptide technology, µSPOT, to determine binding epitopes of SD-specific protein-protein interactions, PPIs. We used our newly developed array screening method to perform positional scans of the defined binding epitopes and deciphered key residues facilitating APP, AJAP1 and PIANP interactions with SD1. Subsequently, this information was combined with in silico screening resulting in highly potent peptide-based modulators of presynaptic GBR, providing promising lead compounds towards development of cognition enhancing therapeutics.
Vita received her BSc in Applied Chemistry from Kaunas University of Technology in Lithuania, and moved to Denmark to pursue a MSc degree in Medicinal Chemistry at University of Copenhagen. In 2016 she started her Ph.D. in Pharmaceutical Sciences under supervision of Professor Kristian Strømgaard. During her Ph.D. and postdoctoral research, she has been a visiting researcher at University of Basel with Professor Bernhard Better. Since 2021, Vita is an Assistant Professor in the group of Professor Kristian Strømgaard at the Department of Drug Design and Pharmacology, University of Copenhagen.
The focus of Vita's research is to study protein-protein interactions, PPIs, within receptor complexes in the brain. She uses high throughput techniques such as SPOT to decipher binding interfaces of various PPIs within GABAB and NMDA receptor complexes, to aid development of in vivo active peptide-based probes with biological and therapeutic relevance.