Structural components of ryanodine responsible for modulation of sarcoplasmic reticulum calcium channel function

William Welch, Alan J. Williams, Andrew Tinker, Kathy E. Mitchell, Pierre Deslongchamps, J. Lamothe, Koert Gerzon, Keshore R. Bidasee, Henry R. Besch, Judith A. Airey, John L. Sutko, Luc Ruest

Research output: Contribution to journalArticle

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Abstract

Comparative molecular field analysis (CoMFA) was used to analyze the relationship between the structure of a group of ryanoids and the modulation of the calcium channel function of the ryanodine receptor. The conductance properties of ryanodine receptors purified from sheep heart were measured using the planar, lipid bilayer technique. The magnitude of the ryanoid- induced fractional conductance was strongly correlated to specific structural loci on the ligand. Briefly, electrostatic effects were more prominent than steric effects. The 10-position of the ryanoid had the greatest influence on fractional conductance. Different regions of the ligand have opposing effects on fractional conductance. For example, steric bulk at the 10-position is correlated with decreased fractional conductance, whereas steric bulk at the 2-position (isopropyl position) is correlated with increased fractional conductance. In contrast to fractional conductance, the 3-position (the pyrrole locus) had the greatest influence on ligand binding, whereas the 10- position had comparatively little influence on binding. Two possible models of ryanodine action, a direct (or channel plug) mechanism and an allosteric mechanism, were examined in light of the CoMFA. Taken together, the data do not appear to be consistent with direct interaction between ryanodine and the translocating ion. The data appear to be more consistent with an allosteric mechanism. It is suggested the ryanoids act by inducing or stabilizing a conformational change in the ryanodine receptor that results in the observed alterations in cation conductance.

Original languageEnglish (US)
Pages (from-to)2939-2950
Number of pages12
JournalBiochemistry
Volume36
Issue number10
DOIs
StatePublished - Mar 11 1997

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Ryanodine
Ryanodine Receptor Calcium Release Channel
Sarcoplasmic Reticulum
Calcium Channels
Modulation
Ligands
Pyrroles
Lipid bilayers
Lipid Bilayers
Static Electricity
Cations
Electrostatics
Sheep
Ions

ASJC Scopus subject areas

  • Biochemistry

Cite this

Welch, W., Williams, A. J., Tinker, A., Mitchell, K. E., Deslongchamps, P., Lamothe, J., ... Ruest, L. (1997). Structural components of ryanodine responsible for modulation of sarcoplasmic reticulum calcium channel function. Biochemistry, 36(10), 2939-2950. https://doi.org/10.1021/bi9623901

Structural components of ryanodine responsible for modulation of sarcoplasmic reticulum calcium channel function. / Welch, William; Williams, Alan J.; Tinker, Andrew; Mitchell, Kathy E.; Deslongchamps, Pierre; Lamothe, J.; Gerzon, Koert; Bidasee, Keshore R.; Besch, Henry R.; Airey, Judith A.; Sutko, John L.; Ruest, Luc.

In: Biochemistry, Vol. 36, No. 10, 11.03.1997, p. 2939-2950.

Research output: Contribution to journalArticle

Welch, W, Williams, AJ, Tinker, A, Mitchell, KE, Deslongchamps, P, Lamothe, J, Gerzon, K, Bidasee, KR, Besch, HR, Airey, JA, Sutko, JL & Ruest, L 1997, 'Structural components of ryanodine responsible for modulation of sarcoplasmic reticulum calcium channel function', Biochemistry, vol. 36, no. 10, pp. 2939-2950. https://doi.org/10.1021/bi9623901
Welch W, Williams AJ, Tinker A, Mitchell KE, Deslongchamps P, Lamothe J et al. Structural components of ryanodine responsible for modulation of sarcoplasmic reticulum calcium channel function. Biochemistry. 1997 Mar 11;36(10):2939-2950. https://doi.org/10.1021/bi9623901
Welch, William ; Williams, Alan J. ; Tinker, Andrew ; Mitchell, Kathy E. ; Deslongchamps, Pierre ; Lamothe, J. ; Gerzon, Koert ; Bidasee, Keshore R. ; Besch, Henry R. ; Airey, Judith A. ; Sutko, John L. ; Ruest, Luc. / Structural components of ryanodine responsible for modulation of sarcoplasmic reticulum calcium channel function. In: Biochemistry. 1997 ; Vol. 36, No. 10. pp. 2939-2950.
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