The muscle-specific
glutathione transferase GSTM2-2 modulates the activity of
ryanodine receptor (RyR)
calcium release channels: it inhibits the activity of cardiac RyR (
RyR2) channels with high affinity and activates skeletal RyR (
RyR1) channels with low affinity. The C terminal domain of GSTM2-2 (GSTM2C) alone physically binds to
RyR2 and inhibits its activity, but it does not bind to
RyR1. We have now used yeast two-hybrid analysis, chemical cross-linking, intrinsic
tryptophan fluorescence and Ca(2+) release studies to determine that the binding site for GSTM2C is in divergent region 3 (D3) of
RyR2. The D3 region encompasses residues 1855-1890 in
RyR2. Specific mutagenesis shows the binding primarily involves electrostatic interactions with residues K1875, K1886, R1887 and K1889, all residues that are present in
RyR2, but not in
RyR1. The significant sequence differences between the D3 regions of
RyR2 and
RyR1 explain why GSTM2-2 specifically inhibits
RyR2. This specific inhibition of
RyR2 could modulate Ca cycling and be useful for the treatment of
heart failure.
RyR2 inhibition during diastole may improve filling of the SR with Ca(2+) and improve contractility.