A Novel Approach in Neuropharmacology: Targeting GABA(A)R-Associated Proteins

• Applicant: Dr. Hans Michael Maric
• Subject Area: Biochemistry ; Biological and Biomimetic Chemistry
• Term: since 2021
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 455237377

The targeted therapy of neuronal disorders requires the selective modulation of dysfunctional neuronal pathways. γ-Aminobutyric acid type A receptors (GABA(A)Rs) as well as glycine receptors are the major mediators of phasic and tonic inhibition in the human brain. These receptors are arranged in functionally highly diverse neuronal structures via associated proteins. The involved proteins and interaction surfaces, and their physiological relevance, however, remain largely unknown. Yet, advancements in neuropharmacology will require a fundamental understanding of these interactions and their underlying signalling pathways. Currently used drugs display limited GABA(A)R subtype specificity and broadly affect receptors in different brain regions and neuronal structures. This lack of specificity causes adverse effects and inherently limits the drug efficacy. Here, I propose to investigate the role of GABA(A)R-associated proteins (GAPs) in synapse maintenance and function and to explore GAP targeting as a means to affect disease-relevant protein complexes in distinct brain regions and discrete neuronal pathways. Recently, I have set up an integrated technology platform that has allowed me to resolve GAP binding sites, commonly short linear motifs within the highly diverse intracellular receptor regions. I have demonstrated that these motifs can be exploited to modulate neurotransmission with a specificity that could not be achieved by orthosteric and allosteric ligands of the receptor itself. Dysfunctional GABA(A)R signalling, as observed in human neurological disorders, can be rescued in mice by genetic manipulation of specific GAP binding motifs. We have recently shown that specific pharmaceutical targeting of these GAPs is feasible in living neurons. Here, I present a research programme devoted to the study of GAPs and their pharmacological targeting. GABA(A)R-GAP interactions will be characterised comprehensively and systematically using our integrated technology setup. Studies in cells including primary neurons will determine the contribution of GAP interactions to synaptic maintenance and function. Importantly, we will develop biomimetic modulators of specific GAP interactions. These will be used to explore, for the first time, specific GAP functions and their neuropharmacological potential.

• DFG Programme: Independent Junior Research Groups