Objective: 

Low blood potassium is a common clinical condition and increases in-hospital mortality. However, much is still unknown regarding how extracellular potassium ([K⁺]e) regulates Ca²⁺ homeostasis.

Methods and results: 

We field stimulated cardiomyocytes and superfused them with normal (5.0mM) and low (2.7mM) potassium. We observed a biphasic response in Ca²⁺ transients with an initial decrease and a later increase. In Ca²⁺ transients obtained in voltage clamped cells, no initial decrease is observed, suggesting a membrane potential-dependent mechanism. When field stimulated cardiomyocytes were incubated in low dose ouabain (0.3 mM) to selectively inhibit NKAa2, the late increase in Ca²⁺ transients was abolished. To examine whether [K⁺]e regulates NCX activity through subsarcolemmal Na⁺ gradients, cardiomyocytes were voltage clamped at -50 mV with low resistance pipettes (1MW) to achieve optimal dialysis, and superfused with a 0 K⁺/0 Ca²⁺ solution. NCX currents were then measured by applying pulses of 2 mM Ca²⁺. NKA was activated by adding 5.0 or 2.7 mM K⁺ to the superfusate, before measuring NCX currents. Experiments were also performed with specific inhibition of NKAa2 by adding low dose ouabain, and the results show that [K⁺]e could regulate NCX activity through establishing subsarcolemmal Na⁺ gradients, and that NKAa2 inhibition abolishes the [K+]e dependency of NCX.

Conclusion: 

We conclude that [K⁺]e regulates Ca²⁺ homeostasis through functional coupling between NKAa2 and NCX.