Biology subjects

Schulz, J. M.

Publications and source records attributed to Schulz, J. M..

5 recordsLinked to original sources

bioRxiv2026

E3 Ligase Ligandalyzer: A Structure-First, Ligand-Centric Platform for E3 Ligase Recruiter Selection

Here, we present E3 Ligase Ligandalyzer Version 1.0, a freely accessible, recruiter-centric web platform for comparative exploration of experimentally resolved E3 ligase-recruiter complexes. The locked Version 1.0 dataset spans 35 E3 ligases, 604 reconciled recruiter entities, and 1,372 active structure-specific recruiter instances across 685 experimentally resolved PDB structures. Recruiters are linked to normalized chemical representations and analyzed using cheminformatics and structure-based workflows to compute physicochemical descriptors, scaffold relationships, aligned binding-pocket views, and solvent-accessible surface area patterns relevant to linker attachment. The platform integrates recruiter-entity, recruiter-instance, scaffold, and ligase views, allowing users to compare experimentally grounded chemical and structural observations without imposing predictive rankings. The platform supports direct transition into downstream degrader-design workflows, including integration with PROTAC Builder (protacbuilder.com). E3 Ligase Ligandalyzer is freely available at https://e3ligandalyzer.com, and the associated code and dataset-generation scripts are available at https://github.com/schurerlab/E3-Ligandalyzer-Scripts.

bioinformatics↗

bioRxiv2025

Pre- and postsynaptic mechanisms of neuronal inhibition assessed through biochemically detailed modelling of GABAB receptor signalling

GABAB receptors (GABABRs) are an important building block in neural activity. Despite their widely hypothesized role in many basic neuronal functions and mental disorder symptomatology, there is a lack of biophysically and biochemically detailed models of these receptors and the way they mediate neuronal inhibition. Here, we developed a computational model for the activation of GABABRs and its effects on the activation of G protein-coupled inwardly rectifying potassium (GIRK) channels as well as inhibition of voltage-gated Ca2+ channels. To ensure the generality of our modelling framework, we fit our model to electrophysiological data including patch-clamp and intracellular recordings that described both pre- and postsynaptic effects of the receptor activation. We validated our model using data on postsynaptic effects of GABABRs on layer V pyramidal cell firing activity ex vivo and in vivo and confirmed the strong impact of dendritic GIRK channel activation on the neuron output. Finally, we reproduced and dissected the effects of a knockout of RGS7 (a G protein signalling protein) on CA1 pyramidal cell electrophysiological properties, which shows the potential of our model in generating insights on genetic manipulations of the GABABR system and related genetic variants. Our model thus provides a flexible tool for biochemically and biophysically detailed simulations of different aspects of GABABR activation that can reveal both foundational principles of neuronal dynamics and brain disorder-associated traits and treatment options.

neuroscience↗

bioRxiv2022

Trans-cellular control of synapse properties by a cell type-specific splicing regulator

The recognition of synaptic partners and specification of synaptic properties are fundamental for the function of neuronal circuits. Terminal selector transcription factors coordinate the expression of terminal gene batteries that specify cell type-specific properties. Moreover, pan-neuronal alternative splicing regulators have been implicated in directing neuronal differentiation. However, the cellular logic of how splicing regulators instruct specific synaptic properties remains poorly understood. Here, we combine genome-wide mapping of mRNA targets and cell type-specific loss-of-function studies to uncover the contribution of the nuclear RNA binding protein SLM2 to hippocampal synapse specification. Focusing on hippocampal pyramidal cells and SST-positive GABAergic interneurons, we find that SLM2 preferentially binds and regulates alternative splicing of transcripts encoding synaptic proteins, thereby generating cell type-specific isoforms. In the absence of SLM2, cell type-specification, differentiation, and viability are unaltered and neuronal populations exhibit normal intrinsic properties. By contrast, cell type-specific loss of SLM2 results in highly selective, non-cell autonomous synaptic phenotypes, altered synaptic transmission, and associated defects in a hippocampus-dependent memory task. Thus, alternative splicing provides a critical layer of gene regulation that instructs specification of neuronal connectivity in a trans-synaptic manner.

neuroscience↗

bioRxiv2020

Sparsification of AP firing in adult-born hippocampal granule cells via voltage-dependent α5-GABAA receptors

GABA can depolarize immature neurons close to the action potential (AP) threshold in development and adult neurogenesis. Nevertheless, GABAergic synapses effectively inhibit AP firing in newborn granule cells of the adult hippocampus as early as 2 weeks post mitosis. The underlying mechanisms are largely unclear. Here we analyzed GABAergic inputs in newborn 2- to 4-week-old hippocampal granule cells mediated by soma-targeting parvalbumin (PV) and dendrite-targeting somatostatin (SOM) interneurons. Surprisingly, both interneuron subtypes activate 5-subunit containing GABAA receptors (5-GABAARs) in young neurons, showing a nonlinear voltage dependence with increasing conductance around the AP threshold. By contrast, in mature cells, PV interneurons mediate linear GABAergic synaptic currents lacking 5-subunits, while SOM-interneurons continue to target nonlinear 5-GABAARs. Computational modelling shows that the voltage-dependent amplification of 5-GABAAR opening in young neurons is crucial for inhibition of AP firing to generate balanced and sparse firing activity, even with depolarized GABA reversal potentials.

neuroscience↗

bioRxiv2019

Dendritic GABAB receptors control nonlinear information transfer along the dendro-somatic axis in layer 5 pyramidal neurons

Dendritic GABAB receptors (GABABRs) mediate a slow form of interhemispheric inhibition. Surprisingly, this inhibition has no detectable effect on the somatic membrane potential of layer 5 pyramidal neurons, whereas the action potential (AP) output is robustly decreased even when the input is proximal to the cell body. To elucidate the underlying mechanisms, we systematically mapped the AP frequency-current (F-I) relationship during dual patch-clamp recordings from soma and apical dendrite. The AP output function was governed by the synergistic interaction between dendritic and somatic compartments as the local input and transfer resistance from dendrite to soma (Kds) depended on the dendritic membrane potential. Thus, Kds doubled at an estimated rate of once per 28.7 mV depolarization due to HCN channel deactivation. In addition, dendritic L-type Ca2+ channels converted individual APs into dendritic Ca2+ spikes causing high-frequency bursts of APs (HFB) during large dendritic depolarization. Activation of dendritic GABABRs greatly reduced both nonlinear mechanisms. While direct block of L-type Ca2+ channels reduced the number of HFBs, K+ channel activation decreased voltage-dependent input and transfer resistances and decreased the AP rate under all conditions. These results highlight the powerful modulation of the input integration in pyramidal neurons by metabotropic receptor-activated K+ channels.

neuroscience↗