Abstract
BackgroundP2Y receptor activation may link the effect of purines to increased maximal in vitro activity of the Na,K-ATPase in rat muscle. The hypothesis that a similar mechanism is present in human skeletal muscle was investigated with membranes from rat and human skeletal muscle.ResultsMembranes purified from rat and human muscles were used in the Na,K-ATPase assay. Incubation with ADP, the stable ADP analogue MeS-ADP and UDP increased the Na+ dependent Na,K-ATPase activity in rat muscle membranes, whereas similar treatments of human muscle membranes lowered the Na,K-ATPase activity. UTP incubation resulted in unchanged Na,K-ATPase activity in humans, but pre-incubation with the antagonist suramin resulted in inhibition with UTP, suggesting that P2Y receptors are involved. The Na,K-ATPase in membranes from both rat and human could be stimulated by protein kinase A and C activation. Thus, protein kinase A and C activation can increase Na,K-ATPase activity in human muscle but not via P2Y receptor stimulation.ConclusionThe inhibitory effects of most purines (with the exception of UTP) in human muscle membranes are probably due to mass law inhibition of ATP hydrolysis. This inhibition could be blurred in rat due to receptor mediated activation of the Na,K-ATPase. The different effects could be related to a high density of ADP sensitive P2Y1 and P2Y13 receptors in rat, whereas the UTP sensitive P2Y11 could be more abundant in human. Alternatively, rat could possesses a mechanism for protein-protein interaction between P2Y receptors and the Na,K-ATPase, and this mechanism could be absent in human skeletal muscle (perhaps with the exception of the UTP sensitive P2Y11 receptor).PerspectiveRat muscle is not a reliable model for purinergic effects on Na,K-ATPase in human skeletal muscle.
Highlights
Purines (ATP and ADP) are released from muscle tissue to the extracellular space during contractions [1] and are potential signalling molecules
In support of this the Na,KATPase activity in membranes isolated from rat muscle is increased by purinergic stimulation and inhibited by P2Y receptor antagonists [4]
Based on the action of agonists and antagonists it was suggested that the purinergic response in rat muscle membranes involves P2Y1, P2Y3/4 and P2Y13 receptors [4]
Summary
Purines (ATP and ADP) are released from muscle tissue to the extracellular space during contractions [1] and are potential signalling molecules. Extracellular purines (0.1 to 1 mM) augments Na,K-ATPase activity, which may be related to stimulation of P2Y1 receptors [3] In support of this the Na,KATPase activity in membranes isolated from rat muscle is increased by purinergic stimulation and inhibited by P2Y receptor antagonists [4]. Based on the action of agonists and antagonists it was suggested that the purinergic response in rat muscle membranes involves P2Y1, P2Y3/4 and P2Y13 receptors [4]. The purines increase both the Na+ affinity (reduced Km) and the maximal in vitro capacity (Vmax) of the Na,K-ATPase by two independent mechanisms: a P2Y receptor-mediated increase in maximal activity, and a receptor independent, but phosphorylation dependent, increase in Na+ affinity [4]. The hypothesis that a similar mechanism is present in human skeletal muscle was investigated with membranes from rat and human skeletal muscle
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