STRUCTURAL COMPONENTS OF RYANODINE RESPONSIBLE FOR MODULATION OF SARCOPLASMIC-RETICULUM CALCIUM-CHANNEL FUNCTION

Comparative molecular field analysis (CoMFA) was used to analyze the r elationship between the structure of a group of ryanoids and the modul ation of the calcium channel function of the ryanodine receptor. The c onductance properties of ryanodine receptors purified from sheep heart were measured using the planar, lipid bilayer technique. The magnitud e of the ryanoid-induced fractional conductance was strongly correlate d to specific structural loci on the ligand. Briefly, electrostatic ef fects were more prominent than steric effects. The 10-position of the ryanoid had the greatest influence on fractional conductance. Differen t regions of the ligand have opposing effects on fractional conductanc e. For example, steric bulk at the 10-position is correlated with decr eased fractional conductance, whereas steric bulk at the 2-position (i sopropyl position) is correlated with increased fractional conductance . In contrast to fractional conductance, the 3-position (the pyrrole l ocus) had the greatest influence on ligand binding, whereas the 10-pos ition had comparatively little influence on binding. Two possible mode ls of ryanodine action, a direct (or channel plug) mechanism and an al losteric mechanism, were examined in light of the CoMFA. Taken togethe r, the data do not appear to be consistent with direct interaction bet ween ryanodine and the translocating ion. The data appear to be more c onsistent with an allosteric mechanism. It is suggested the ryanoids a ct by inducing or stabilizing a conformational change in the ryanodine receptor that results in the observed alterations in cation conductan ce.