The inhibitory glutathione transferase M2-2 binding site is located in divergent region 3 of the cardiac ryanodine receptor

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• 作者：Dan Liu ; Ruwani Hewawasam ; Yamuna Karunasekara ; Marco G. Casarotto ; Angela F. Dulhunty¹ ; Philip G. Board¹ ; ^{Philip.Board@anu.edu.au}
• 关键词：Glutathione transferase GSTM2-2 ; Cardiac RyR2 channels ; Divergent region 3 of RyRs ; Skeletal RyR1 channels ; Inhibition of RyR2 channels ; Yeast two hybrid analysis
• 刊名：Biochemical Pharmacology
• 出版年：2012
• 期刊代码：2_00062952
• 类别：pha
• 出版时间：1 June, 2012
• 卷：83
• 期：11
• 页码：1523-1529
• 文件大小：710 K

摘要

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 Ca²⁺ 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 Ca²⁺ and improve contractility.