Function, pharmacology and pathophysiology of the TRPC1 channel
Membrane channels containing TRPC1 have been suggested to be activated, among other pathways, by mechanical stress on the cell membrane, thus forming stretch-activated channels (SACs), and leading to damaging influx of Ca2+ in several diseases. Prominent related pathological conditions include muscular dystrophy (encompassing dystrophic cardiomyopathy) with an abnormal membrane stress sensitivity and cardiac hypertrophy during pressure overload (due to mechanical overload of the cells). TRPC1 has been reported to heteromultimerize with a variety of TRP channels and interact with several other proteins.
Within TransCure project 2A, efforts are ongoing to validate TRPC1 as a therapeutic target and as a putative subunit of SACs. This involves confocal Ca2+ imaging experiments in skeletal muscle myotubes and cardiomyocytes isolated from wild-type and dystrophic mdx mice, in combination with siRNA approaches targeting various TRP channels implicated in stretch-activation, including TRPC1 (for which a knockout mouse model is also available). In parallel and in a joint effort with the Hediger group, a cellular screening assay is being established in order to identify and develop inhibiting compounds in collaboration with TransCure chemists (Reymond and Lochner group). Most promising new compounds will be evaluated in the cellular models mentioned above, but also in animal models of skeletal and cardiac muscle disease.
University of Bern, Department of Physiology
|Niggli Ernst (PI)
Lorin Charlotte (Postdoctoral Fellow)
Vögeli Isabelle Astrid (Postdoctoral Fellow)