Although lithium ion substitutes poorly for potassium ion in the reaction cycle of (Na+ + K+)-ATPase (ATP phosphohydrolase, EC 220.127.116.11), it consistently activated this enzyme in the presence of sodium and potassium. In contrast, rubidium ion, a much more effective substitute for potassium than lithium, was generally inhibitory in the presence of sodium and potassium. Li+ did not appear to activate the enzyme by stimulating its phosphorylation from ATP. Rather, Na+ was required for Li+ to stimulate ATPase activity, and Li+ directly (though weakly) stimulated dephosphorylation. Under conditions such that increasing concentrations of K+ and Rb+ inhibited turnover of the enzyme, Li+ stimulated its activity above values observed with K+ or Rb+. It appears that Li+ stimulates the turnover of the ATPase by triggering its dephosphorylation and dissociating rapidly from the dephospho-enzyme, thus allowing the enzyme to rephosphorylate readily. With Rb+ the stability of the dephospho-enzyme[unknown]rubidium complex hinders subsequent rephosphorylation of the enzyme and thus inhibits its turnover. Because Li+ and Rb+ respectively stimulate and inhibit (Na+ + K+)-ATPase relative to its activity in the presence of Na+ and K+, they may hyperpolarize or depolarize nerve cells in corresponding fashion. It is suggested that these actions of lithium and rubidium on the turnover of (Na+ + K+)-ATPase may be involved in their pharmacological actions.
ACKNOWLEDGMENT The authors thank Mrs. Marilyn Turnbow for excellent technical assistance.
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