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Interactive effects of Na and K in killing by human natural killer cells
L C Schlichter1, I C MacCoubrey
1Department of Physiology, University of Toronto, Ontario, Canada.
Abstract:
Contact-mediated lysis by human natural killer cells is inhibited by a number of drugs that block the predominant K channel. In this study we have further examined the role of the K channel and the interactions between passive K and Na transport in killing. Low external Na-inhibited killing and inhibition were not due to reduce inward current through the Na channels in the target cell. A role for the Na/H antiport is suggested since amiloride inhibited killing in a dose-dependent manner that was competitive with external Na. Depolarizing the killer cell with elevated external K did not inhibit killing. On the contrary, high K0 reduced the inhibition caused by low Na0 and by the K-channel blockers quinidine, verapamil, and retinoic acid. Hyperpolarizing the killer cell with low K0 or valinomycin inhibited killing. Valinomycin, which should prevent the depolarization caused by K-channel block, did not reverse the effect of the blockers quinidine, verapamil, and 4-aminopyridine. Hence, the primary role of the K channels during killing is not maintain the negative membrane potential. On the contrary, depolarization may promote killing under conditions where killing is submaximal.
Insights
Natural killer (NK) cell killing relies on ion transport. Depolarizing the killer cell may enhance NK cell activity, contrary to previous beliefs about potassium channels.
Area of Science:
- Immunology
- Cellular Biology
- Biophysics
Background:
- Contact-mediated lysis by human natural killer (NK) cells is crucial for immune surveillance.
- NK cell cytotoxicity is known to be modulated by ion channel activity, particularly potassium (K) channels.
Purpose of the Study:
- To investigate the role of K channels and the interplay between passive K and sodium (Na) transport in NK cell-mediated killing.
- To determine if membrane potential influences NK cell cytotoxicity.
Main Methods:
- Examined the effects of varying external Na and K concentrations on NK cell killing.
- Utilized K-channel blockers (quinidine, verapamil, 4-aminopyridine) and Na/H antiport inhibitor (amiloride).
- Assessed NK cell activity under conditions of depolarization (high external K) and hyperpolarization (low external K, valinomycin).
Main Results:
- Low external Na inhibited NK cell killing, suggesting a role for Na/H antiport.
- Elevated external K (depolarization) did not inhibit killing and reduced the effect of K-channel blockers.
- Hyperpolarization inhibited killing, and valinomycin did not reverse K-channel blocker-induced inhibition.
Conclusions:
- The primary role of K channels in NK cell killing is not to maintain a negative membrane potential.
- Depolarization of the killer cell may promote cytotoxicity, especially when submaximal.