510031 Vortragsreihe Medizinische Forschung: "How cells gate chloride transport: from channel structure to signalling pathways, osmoregulation and brain disease" (V+Ko) (WiSe 2026/2027)

How cells gate chloride transport: from channel structure to signalling pathways, osmoregulation and brain disease

Abstract:

Volume-regulated anion channels (VRACs) mediate the transport of chloride and organic osmolytes and play important roles in cellular volume regulation and diverse physiological processes, including apoptosis, insulin signalling and neuron–glia communication. Dysregulation of VRAC activity has been implicated in neurological disorders. Following our identification of LRRC8 proteins as essential components of VRACs, we have focused on understanding the molecular mechanisms underlying channel activation and regulation. However, how changes in cell volume and physiological signals control VRAC gating has remained poorly understood.
In this talk, I will present recent insights into the structural and signalling mechanisms controlling VRAC activity. Using electrophysiology, FRET-based approaches and cryo-electron microscopy, we identified a regulatory hotspot in the intracellular subdomain of LRRC8A that couples conformational rearrangements of the cytosolic leucine-rich repeat domains to channel opening. Furthermore, we uncovered a signalling pathway in which the orphan G protein-coupled receptor GPRC5B recruits the Src-family kinase Fyn to inhibit VRAC activation through a specific tyrosine residue in LRRC8A. This pathway interferes with the conformational changes required for channel opening and is modulated by MLC1, a protein implicated in megalencephalic leukoencephalopathy, linking VRAC regulation to brain disease.
Together, these findings reveal how intrinsic structural mechanisms and cellular signalling pathways converge to regulate VRAC gating, providing new insights into the molecular control of chloride transport and its dysfunction in neurological disease.

Der Vortrag wird online via Zoom übertragen.
Promovierende werden gebeten im Zoom-Meeting mit Ihrem eindeutig zuordenbaren Namen zu erscheinen.

Zugangsdaten zur Zoom-Videokonferenz:
https://uni-bielefeld.zoom-x.de/j/61928684463?pwd=aXowCpzMJceIJeLuzpt8HcsBMQew1K.1

Meeting-ID: 619 2868 4463
Passwort: 279111