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Untersuchung der Konformationsdynamik von TRPC6 mit Hochgeschwindigkeits-Atomkraftmikroskopie
- Abstract
- Transient receptor potential canonical (TRPC) channels are calcium permeable ion channels found both in excitable and non-excitable cells. TRPC channels are activated by diacylglycerol (DAG), a product generated in the phospholipase C (PLC) pathway following the cleavage of phosphatidylinositol 4,5-bisphosphate (PIP2). Notably, although all TRPC channels are involved in (patho)physiological processes, only TRPC6 has been identified as playing a pivotal role in the development of a severe kidney disease known as focal segmental glomerulosclerosis (FSGS). FSGS is characterized by continuous calcium leakage through TRPC6, which disturbs ion homeostasis within glomerular cells, ultimately resulting in glomerular sclerosis. Recent cryo-electron microscopy (cryo-EM) studies of TRPC61–3 could obtain only closed-channel structures and do not give insights into the dynamics of channel gating even in presence of activators. However, gaining an understanding of the gating mechanism of the TRPC6 channel will enhance our comprehension of its pathophysiological significance. Furthermore, it will establish a foundation for developing pharmacological strategies to regulate the channel within native tissues. Electrophysiological analysis of TRPC6 behavior on a single channel level showed a short-lived open state of the channel.4 Consequently, we hypothesized that the channel behavior is the main obstacle in gaining insights into the gating mechanism of TRPC6 channels during cryo-EM. High-speed atomic force microscopy (HS-AFM), a state-of-the-art technique, has gained high attention in recent years especially in studying ion channel gating. This technique allows high-resolution and time resolved topographic images of a sample by scanning its surface. Recently the group of Prof. Dr. Scheuring, successfully employed HS-AFM to study the dynamics in TRPV25 and TRPV36 ion channels. To gain a comprehensive understanding of TRPC6 and understand the behavior of the channel in native tissue we will study the dynamics of channel gating upon stimulation with different agonists using HS-AFM.
- Keywords
- Kanalöffnung
- Ligandabhängige Kanalaktivierung
- Rasterkraftmikroskopie
- TRPC6
- Project Leader:
- Baron Jasmin
- Duration:
- 01.10.2024-30.09.2026
- Programme:
- Doc (Doktorand*innen*enprogramm der Österreichischen Akademie der Wissenschaften)
- Type of Research
- basic research
- Staff
- Baron, Jasmin, Project Leader
- Wiedner, Patrick, Co-worker
- Groschner, Klaus, Co-worker
- Tiapko, Oleksandra, Co-worker
- Schindl, Rainer, Co-worker
- MUG Research Units
- Division of Medical Physics and Biophysics
- Gottfried Schatz Research Center (for Cell Signaling, Metabolism and Aging)
- Project partners
-
Institute for Molecular Biosciences, Austria
Contact person: Sandro Keller; -
, Austria
Contact person: Johannes Preiner, Andreas Karner;