Muscle-specific GSTM2-2 on the luminal side of the sarcoplasmic reticulum modifies RyR ion channel activity

Lan Wei, Yasser Abdellatif, Dan Liu, Takashi Kimura, Marjorie Coggan, Esther M. Gallant, Nicole BEARD, Philip Board, Angela F. Dulhunty

Research output: Contribution to journalArticle

11 Citations (Scopus)

Abstract

We show that a glutathione transferase (GST) protein, which is recognised by an antibody against the muscle-specific human GSTM2-2 (hGSTM2-2), is associated with the lumen of the sarcoplasmic reticulum (SR) of cardiac muscle, but not skeletal muscle. We further show that hGSTM2-2 modifies both cardiac and skeletal ryanodine receptor (RyR) activity when it binds to the luminal domain of the RyR channel complex. The properties of hGSTM2-2 were compared with those of the calsequestrin (CSQ), a Ca2+ binding protein also present in the lumen of the SR which, like GSTM2-2, contains a thioredoxin-fold structure and modifies RyR activity (Wei, L., Varsanyi, M., Dulhunty, A. F., Beard, N. A. (2006). The Biophysical Journal, 91, 1288–1301). The glutathione transferase activity of hGSTM2-2 is strong, while CSQ is essentially inactive. Conversely CSQ is a strong Ca2+ binder, but hGSTM2-2 is not. The effects of luminal hGSTM2-2 on RyR activity differ from those of CSQ in that hGSTM2-2 activates RyRs by increasing their open probability and conductance and the effects are independent of luminal Ca2+ concentration. The results suggest that GSTM2-2 can interact with specific luminal sites on the RyR complex and that the interaction is likely to be within the pore of the RyR channel. The differences between the effects of CSQ and hGSTM2-2 suggest that the thioredoxin fold is not a major determinant of the luminal actions of either protein. The results indicate that GSTM2-2 is a novel luminal regulator of the RyR channels in the heart.
Original languageEnglish
Pages (from-to)1616-1628
Number of pages13
JournalThe International Journal of Biochemistry and Cell Biology
Volume40
Issue number8
DOIs
Publication statusPublished - 2008
Externally publishedYes

Fingerprint

Ryanodine Receptor Calcium Release Channel
Sarcoplasmic Reticulum
Calsequestrin
Ion Channels
Muscle
Muscles
Thioredoxins
Glutathione Transferase
Human Activities
Binders
Myocardium
Carrier Proteins
Skeletal Muscle
Proteins
Antibodies

Cite this

Wei, Lan ; Abdellatif, Yasser ; Liu, Dan ; Kimura, Takashi ; Coggan, Marjorie ; Gallant, Esther M. ; BEARD, Nicole ; Board, Philip ; Dulhunty, Angela F. / Muscle-specific GSTM2-2 on the luminal side of the sarcoplasmic reticulum modifies RyR ion channel activity. In: The International Journal of Biochemistry and Cell Biology. 2008 ; Vol. 40, No. 8. pp. 1616-1628.
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abstract = "We show that a glutathione transferase (GST) protein, which is recognised by an antibody against the muscle-specific human GSTM2-2 (hGSTM2-2), is associated with the lumen of the sarcoplasmic reticulum (SR) of cardiac muscle, but not skeletal muscle. We further show that hGSTM2-2 modifies both cardiac and skeletal ryanodine receptor (RyR) activity when it binds to the luminal domain of the RyR channel complex. The properties of hGSTM2-2 were compared with those of the calsequestrin (CSQ), a Ca2+ binding protein also present in the lumen of the SR which, like GSTM2-2, contains a thioredoxin-fold structure and modifies RyR activity (Wei, L., Varsanyi, M., Dulhunty, A. F., Beard, N. A. (2006). The Biophysical Journal, 91, 1288–1301). The glutathione transferase activity of hGSTM2-2 is strong, while CSQ is essentially inactive. Conversely CSQ is a strong Ca2+ binder, but hGSTM2-2 is not. The effects of luminal hGSTM2-2 on RyR activity differ from those of CSQ in that hGSTM2-2 activates RyRs by increasing their open probability and conductance and the effects are independent of luminal Ca2+ concentration. The results suggest that GSTM2-2 can interact with specific luminal sites on the RyR complex and that the interaction is likely to be within the pore of the RyR channel. The differences between the effects of CSQ and hGSTM2-2 suggest that the thioredoxin fold is not a major determinant of the luminal actions of either protein. The results indicate that GSTM2-2 is a novel luminal regulator of the RyR channels in the heart.",
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Muscle-specific GSTM2-2 on the luminal side of the sarcoplasmic reticulum modifies RyR ion channel activity. / Wei, Lan; Abdellatif, Yasser; Liu, Dan; Kimura, Takashi; Coggan, Marjorie; Gallant, Esther M.; BEARD, Nicole; Board, Philip; Dulhunty, Angela F.

In: The International Journal of Biochemistry and Cell Biology, Vol. 40, No. 8, 2008, p. 1616-1628.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Muscle-specific GSTM2-2 on the luminal side of the sarcoplasmic reticulum modifies RyR ion channel activity

AU - Wei, Lan

AU - Abdellatif, Yasser

AU - Liu, Dan

AU - Kimura, Takashi

AU - Coggan, Marjorie

AU - Gallant, Esther M.

AU - BEARD, Nicole

AU - Board, Philip

AU - Dulhunty, Angela F.

PY - 2008

Y1 - 2008

N2 - We show that a glutathione transferase (GST) protein, which is recognised by an antibody against the muscle-specific human GSTM2-2 (hGSTM2-2), is associated with the lumen of the sarcoplasmic reticulum (SR) of cardiac muscle, but not skeletal muscle. We further show that hGSTM2-2 modifies both cardiac and skeletal ryanodine receptor (RyR) activity when it binds to the luminal domain of the RyR channel complex. The properties of hGSTM2-2 were compared with those of the calsequestrin (CSQ), a Ca2+ binding protein also present in the lumen of the SR which, like GSTM2-2, contains a thioredoxin-fold structure and modifies RyR activity (Wei, L., Varsanyi, M., Dulhunty, A. F., Beard, N. A. (2006). The Biophysical Journal, 91, 1288–1301). The glutathione transferase activity of hGSTM2-2 is strong, while CSQ is essentially inactive. Conversely CSQ is a strong Ca2+ binder, but hGSTM2-2 is not. The effects of luminal hGSTM2-2 on RyR activity differ from those of CSQ in that hGSTM2-2 activates RyRs by increasing their open probability and conductance and the effects are independent of luminal Ca2+ concentration. The results suggest that GSTM2-2 can interact with specific luminal sites on the RyR complex and that the interaction is likely to be within the pore of the RyR channel. The differences between the effects of CSQ and hGSTM2-2 suggest that the thioredoxin fold is not a major determinant of the luminal actions of either protein. The results indicate that GSTM2-2 is a novel luminal regulator of the RyR channels in the heart.

AB - We show that a glutathione transferase (GST) protein, which is recognised by an antibody against the muscle-specific human GSTM2-2 (hGSTM2-2), is associated with the lumen of the sarcoplasmic reticulum (SR) of cardiac muscle, but not skeletal muscle. We further show that hGSTM2-2 modifies both cardiac and skeletal ryanodine receptor (RyR) activity when it binds to the luminal domain of the RyR channel complex. The properties of hGSTM2-2 were compared with those of the calsequestrin (CSQ), a Ca2+ binding protein also present in the lumen of the SR which, like GSTM2-2, contains a thioredoxin-fold structure and modifies RyR activity (Wei, L., Varsanyi, M., Dulhunty, A. F., Beard, N. A. (2006). The Biophysical Journal, 91, 1288–1301). The glutathione transferase activity of hGSTM2-2 is strong, while CSQ is essentially inactive. Conversely CSQ is a strong Ca2+ binder, but hGSTM2-2 is not. The effects of luminal hGSTM2-2 on RyR activity differ from those of CSQ in that hGSTM2-2 activates RyRs by increasing their open probability and conductance and the effects are independent of luminal Ca2+ concentration. The results suggest that GSTM2-2 can interact with specific luminal sites on the RyR complex and that the interaction is likely to be within the pore of the RyR channel. The differences between the effects of CSQ and hGSTM2-2 suggest that the thioredoxin fold is not a major determinant of the luminal actions of either protein. The results indicate that GSTM2-2 is a novel luminal regulator of the RyR channels in the heart.

KW - Ryanodine receptor

KW - sarcoplasmic reticulum calcium handling

KW - muscle

KW - Calcium Channels

U2 - 10.1016/j.biocel.2007.12.019

DO - 10.1016/j.biocel.2007.12.019

M3 - Article

VL - 40

SP - 1616

EP - 1628

JO - International Journal of Biochemistry and Cell Biology

JF - International Journal of Biochemistry and Cell Biology

SN - 1357-2725

IS - 8

ER -