title: Structural components of ryanodine responsible for modulation of sarcoplasmic reticulum calcium channel function.
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.
authors.affiliation: Department of Biochemistry, University of Nevada, Reno 89557, USA. welch@scs.unr.edu
authors.forename: W
authors.initials: W
authors.lastname: Welch
authors.forename: A J
authors.initials: AJ
authors.lastname: Williams
authors.forename: A
authors.initials: A
authors.lastname: Tinker
authors.forename: K E
authors.initials: KE
authors.lastname: Mitchell
authors.forename: P
authors.initials: P
authors.lastname: Deslongchamps
authors.forename: J
authors.initials: J
authors.lastname: Lamothe
authors.forename: K
authors.initials: K
authors.lastname: Gerzon
authors.forename: K R
authors.initials: KR
authors.lastname: Bidasee
authors.forename: H R
authors.initials: HR
authors.lastname: Besch
authors.forename: J A
authors.initials: JA
authors.lastname: Airey
authors.forename: J L
authors.initials: JL
authors.lastname: Sutko
authors.forename: L
authors.initials: L
authors.lastname: Ruest
mesh_terms: D000494:Allosteric Regulation; D000818:Animals; D015220:Calcium Channels / Q000378:metabolism*; D004553:Electric Conductivity; D006146:Guanidines / Q000494:pharmacology; D008051:Lipid Bilayers / Q000378:metabolism; D009682:Magnetic Resonance Spectroscopy; D013058:Mass Spectrometry; D008958:Models, Molecular; D015394:Molecular Structure; D009124:Muscle Proteins / Q000378:metabolism*; D009206:Myocardium / Q000378:metabolism; D011485:Protein Binding; D011487:Protein Conformation; D011758:Pyrroles / Q000494:pharmacology; D012433:Ryanodine / Q000031:analogs & derivatives / Q000737:chemistry / Q000494:pharmacology*; D019837:Ryanodine Receptor Calcium Release Channel; D012519:Sarcoplasmic Reticulum / Q000737:chemistry*; D012756:Sheep
chemical_list: D015220:Calcium Channels; D006146:Guanidines; D008051:Lipid Bilayers; D009124:Muscle Proteins; D011758:Pyrroles; D019837:Ryanodine Receptor Calcium Release Channel; D012433:Ryanodine