Malfunction and overexpression of the calcium channel TRPC1 have been found associated with skeletal and cardiac muscle dystrophy, hypertension-induced cardiac hypertrophy and heart failure. Moreover, TRPCs may also be involved in tumorigenesis and metastatic proliferation. Although a specific pharmacology for this putative therapeutic target is lacking, low-affinity inhibitors binding to TRPC1, such as 2-APB and SKF-96365, have been described.

We will examine these low-affinity inhibitors for their ability to interfere with stretch-activated calcium signals and damage in normal and dystrophic muscle cells. With a newly developed fluorescence-based assay for TRPC1 function, we will characterize the available low-affinity inhibitors and identify compounds that are structurally similar (see project 10A).

Finally, we plan to find binding and heteromultimerization partners of TRPC1 that are prevalent in normal and diseased muscle. Most promising new compounds will be characterized in cellular and animal models of muscle disease and tumorigenesis (see project 5).