Prof. Steffen Hering

Probing the role of voltage sensors in calcium channel modulation by agonists and inhibitors.
Opening of voltage-gated calcium channels (CaV) contributes to membrane depolarisation and initiates the generation and propagation of electrical impulses, sensory processes, muscle contraction, secretion of hormones and neurotransmitters, cell differentiation and gene expression, and myocardial automaticity. These channels represent highly sophisticated molecular machines that open and closed in response to changes in the membrane potential. Their pore-forming subunit (α1) is composed of four concatenated domains (I - IV). Each domain has 6 transmembrane segments (S1-S6). Segments IS4-IVS4 carry charged amino acids and sense changes of the membrane voltage. There is evidence that individual VS (IS4-IVS4) have a different impact on gating (Beyl et al. 2012, Pantazis et al. 2014, Beyl et al. 2014, 2015). Here we ask the question how individual voltage sensors contribute to CaV inhibition by calcium antagonists or activation by agonists. Hence, CaV inhibition and activation is modulated by channel gating and VS in different domains are expected to influence this process individually. Our studies are not limited to CaV, we aim to investigate the role of VS in activation/inhibition of bacterial sodium channels and HERG. We will use conventional patch clamp, photo-pharmacology, site directed mutagenesis, molecular modeling and voltage clamp fluorometrie. The study will be performed in close collaboration with the Molecular Modeling Lab of Anna Weinzinger and the labs of Harald Janoviak (photo pharmacology), Nuno Maulide (compound synthesis) and international partners.

GABA-receptor modulation via the VA binding pocket.
Valerenic acid (VA) - a natural product found in common Valerian - allosterically modulates γ-aminobutyric (GABA) type A (GABAA) receptors and causes anxiolysis and anticonvulsant effects (Khom et al., 2007, Benke et al., 2009, Hintersteiner et al., 2014). We have recently identified a putative binding site of VA on the α-/β+ interface of GABAA receptors, and perform currently SAR studies on a set of VA derivatives and analogs. The available X-ray structure and existing homology models will enable ligand- and structure-based design of novel small molecule β2-/β3-subunit selective GABAA modulators. Synthesis of novel selective ligands will be guided by in vitro and in vivo studies. This project will be pursued in collaboration with the groups of Marko Mihovilovic (compound synthesis), Nuno Maulide (compound synthesis), Gerhard Ecker (QSAR, SAR, docking), Gaia Novarino (disease models) and Thierry Langer (QSAR, SAR, docking).