Abstract
Quercetin had a biphasic effect on Ca2+ uptake and calcium-stimulated ATP hydrolysis in isolated cardiac sarcoplasmic reticulum (SR). Stimulation of Ca2+ATPase was observed at low quercetin concentrations (<25 microM) followed by inhibition at higher concentrations. The effects were dependent upon the SR protein concentration, the MgATP concentration, and intact phospholamban regulation of cardiac Ca2+ATPase. Only the inhibitory effects at higher quercetin concentrations were observed in skeletal muscle SR which lacks phospholamban and in cardiac SR treated to remove phospholamban regulation. Stimulation was additive with monoclonal antibody 1D11 (directed against phospholamban) at submaximal antibody concentrations; however, the maximal antibody and quercetin stimulation were identical. Quercetin increased the calcium sensitivity of the Ca2+ATPase like that observed with phosphorylation of phospholamban or treatment with monoclonal antibody 1D11. In addition, low concentrations of quercetin increased the steady-state formation of phosphoenzyme from ATP or Pi, but higher quercetin decreased phosphoenzyme levels. Quercetin, even under stimulatory conditions, was a competitive inhibitor of ATP, but appears to relieve the Ca2+ATPase from phospholamban inhibition, thereby, producing an activation. The subsequent inhibitory action of higher quercetin concentrations results from competition of quercetin with the nucleotide binding site of the Ca2+ATPase. The data suggest that quercetin interacts with the nucleotide binding site to mask phospholamban's inhibition of the SR Ca2+ATPase and suggests that phospholamban may interact at or near the nucleotide binding site.
Highlights
In cardiac and skeletal muscle, the sarcoplasmic reticulum (SR)1 Ca2ϩATPase is responsible for the reuptake of calcium into the SR to allow relaxation
Using an estimate of 4.5 nmol of Ca2ϩATPase/mg of skeletal muscle SR (Shoshan and MacLennan, 1981; Bishop et al, 1987), half-maximal inhibition of skeletal muscle SR Ca2ϩATPase occurred at a ratio of 1778 nmol of Q/nmol of Ca2ϩATPase, which is identical to the value calculated above for cardiac SR
Quercetin’s Interaction with Ca2ϩATPase—The results show that the enzymatic activity of cardiac SR Ca2ϩATPase, but not of skeletal muscle SR Ca2ϩATPase, is stimulated at submicromolar Ca2ϩ by low concentrations of quercetin
Summary
Quercetin (Q), a bioflavanoid, acts as a inhibitor of numerous enzymes involved in energy conversion reactions (Racker, 1986), phosphodiesterase (Kuppasamy and Das, 1992), and numerous protein kinases (Vlahos et al, 1994). It is an inhibitor of skeletal muscle Ca2ϩATPase (Shoshan and MacLennan, 1981; Fischer et al, 1987) with an IC50 of 12 M in 45Ca2ϩ uptake experiments. Evidence suggesting that quercetin’s biphasic effects result from its interaction with the nucleotide binding site on cardiac SR Ca2ϩATPase is presented. Stimulation appears to result from the disruption or masking of PLB’s inhibitory effect on the Ca2ϩATPase, while the inhibitory effect at higher concentrations is like that observed in skeletal muscle SR
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