S-Adenosyl-l-methionine activates the cardiac ryanodine receptor.
S-Adenosyl-l-methionine (SAM) is the biological methyl-group donor for the enzymatic methylation of numerous substrates including proteins. SAM has been reported to activate smooth muscle derived ryanodine receptor calcium release channels. Therefore, we examined the effects of SAM on the cardiac isoform of the ryanodine receptor (RyR2). SAM increased cardiac sarcoplasmic reticulum [(3)H]ryanodine binding in a concentration-dependent manner by increasing the affinity of RyR2 for ryanodine. Activation occurred at physiologically relevant concentrations. SAM, which contains an adenosine moiety, enhanced ryanodine binding in the absence but not in the presence of an ATP analogue. S-Adenosyl-l-homocysteine (SAH) is the product of the loss of the methyl-group from SAM and inhibits methylation reactions. SAH did not activate RyR2 but did inhibit SAM-induced RyR2 activation. SAH did not alter adenine nucleotide activation of RyR2. These data suggest SAM activates RyR2 via a site that interacts with, but is distinct from, the adenine nucleotide binding site.
Kampfer
Angela J
AJ
School of Applied Physiology, Georgia Institute of Technology, 113 Weber Building, 281 Ferst Drive, Atlanta, GA 30332, USA.
Balog
Edward M
EM
D000255:Adenosine Triphosphate / Q000031:analogs & derivatives; D000818:Animals; D006321:Heart; D008745:Methylation; D012433:Ryanodine / Q000378:metabolism; D019837:Ryanodine Receptor Calcium Release Channel / Q000187:drug effects / Q000378:metabolism*; D012436:S-Adenosylmethionine / Q000378:metabolism* / Q000494:pharmacology
D019837:Ryanodine Receptor Calcium Release Channel; D012433:Ryanodine; D012436:S-Adenosylmethionine; D000255:Adenosine Triphosphate