Modulation of the skeletal muscle Ca2+ release channel/ryanodine receptor by adenosine and its metabolites: a structure-activity approach.
Activation of ryanodine receptor (RyR) from skeletal muscle sarcoplasmic reticulum by adenosine and adenosine's metabolites was studied. The purines tested increased the [3H]-ryanodine binding as follows: xanthine>adenosine>adenine >inosine>/=uric acid>hypoxanthine. The enhanced [3H]-ryanodine binding did not involve change in the RyR-Ca(2+) sensitivity and was due mainly to lower values in the affinity constant (K(d)) that corresponded with an increase in the association rate constant (K(+1)). [3H]-ryanodine maximum binding (B(max)) was much less affected. Adenosine and inosine effects were dependent on the presence beta-glycosidic bond within the ribose ring, since the combination of adenine or hypoxanthine with ribose was not able to emulate the nucleosides' original activation. Competition experiments with AMP-PCP, a non-hydrolyzable analogue of ATP, evidenced a nucleotide's inhibitory influence on the adenosine and xanthine activation of the RyR. As a result of a Quantitative Structure-Activity Relationship (QSAR) study, we found a significant correlation between the modulation by adenosine and its metabolites on RyR activity and the components of their calculated dipole moment vector. Our results show that the ribose moiety and the dipole moment vector could be factors that make possible the modulation of the RyR activity by adenosine and its metabolites.
Butanda-Ochoa
Armando
A
Departamento de Neurobiología Celular y Molecular, Instituto de Neurobiología, UNAM, Juriquilla Querétaro 76001, Apdo.Postal 1-1141, Mexico.
Höjer
Germund
G
Díaz-Muñoz
Mauricio
M
D000241:Adenosine / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology*; D000818:Animals; D001667:Binding, Competitive; D002118:Calcium / Q000494:pharmacology; D018656:Muscle Fibers, Fast-Twitch / Q000737:chemistry; D018482:Muscle, Skeletal / Q000737:chemistry* / Q000378:metabolism; D011485:Protein Binding / Q000187:drug effects; D011687:Purines / Q000494:pharmacology; D011817:Rabbits; D011869:Radioligand Assay; D012433:Ryanodine / Q000037:antagonists & inhibitors* / Q000378:metabolism; D019837:Ryanodine Receptor Calcium Release Channel / Q000187:drug effects* / Q000378:metabolism; D012519:Sarcoplasmic Reticulum / Q000737:chemistry; D013329:Structure-Activity Relationship
D011687:Purines; D019837:Ryanodine Receptor Calcium Release Channel; D012433:Ryanodine; D000241:Adenosine; D002118:Calcium