Receptor Signaling Lab

GPCR activation is triggered by binding of a ligand (e.g. adrenaline, glutamate) to a specific site of a receptor. This is followed by a conformational change in the receptor, which enables it to bind to and activate G-proteins. We have developed methods to monitor these signalling events via fluorescence microscopy, and we aim to study where and when in a cell these signals occur. We use techniques to trigger receptor activation by light to monitor signaling with sub-millisecond resolution. We are also working on techniques to adapt such measurements to high throughput screening in order to search for compounds with unusual signalling properties, which might make them new classes of drugs with only a subset of effects compared to conventional drugs.

Cyclic adenosine monophosphate (cAMP) is a second messenger downstream of GPCR activation, which plays an important role in many physiological processes, ranging from regulation of heartbeat and force to synaptic plasticity. Although cAMP appears to be a freely diffusible substance, recent evidence suggests that it may act in cells in a highly localized manner. We are attempting to visualize such local effects and are searching for mechanisms that might lead to the postulated nano-compartments. To do so, we use models ranging from the design and expression of specific cAMP sensor proteins to studies in transgenic fly and mouse models, where we attempt to image local cAMP signals.

GPCRs can form supramolecular complexes (i.e. di-/oligomers) on the cell surface. However, their size, nature and dynamics as well as their physiological and pharmacological implications are still largely unknown. We focus on investigating the dimerization of receptors (especially adrenergic, opiate and chemokine) on the surface of intact cells as well as evaluating the role of dimerization on receptor activation and downstream signalling. We do so by a variety of biochemical and microscopic techniques, notably brightness analysis and single particle microscopy.