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. Author manuscript; available in PMC: 2010 Dec 1.
Published in final edited form as: Nat Chem Biol. 2010 May 9;6(6):424–432. doi: 10.1038/nchembio.368

Figure 2.

Figure 2

Ryanodine receptor antagonists act as GC proteostasis regulators. (a) Small molecules that inhibit the RyRs enhance folding and trafficking of the L444P GC protein in L444P fibroblasts. The significant increase in endo H resistant post-ER GC glycoform when compared to the vehicle controls reflects increased GC proteostasis. Quantification of GC bands is shown in the bar graphs at the bottom of (a). (b) Diltiazem 1, dantrolene 3 and DHBP 4 increase L444P GC enzyme activity (lysed cell activity assay), normalized to the vehicle controls (*, p<0.001). The verapamil 2 data, reported previously12, is included for comparison. (c) Indirect immunofluorescence microscopy of GC in L444P fibroblasts reveals that dantrolene 3 treatment enhances GC staining (green) and colocalization between GC and LAMP2 (artificially colored white). The experiments were repeated three times. (d) Dantrolene 3 increases WT and N370S GC enzyme activity (intact cell assay) in patient-derived fibroblasts, normalized to the vehicle control (*, p<0.001). Data in (b), and (d) are reported as mean ± SEM, statistical significance was evaluated using a two-tailed Student’s t-Test.