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Activation of the cAMP-protein kinase A pathway facilitates Na⁺ translocation by the Na⁺-K⁺ pump in guinea-pig ventricular myocytes

Jens Kockskämper, Simone Erlenkamp and Helfried G. Glitsch

1. The effects of the adenylyl cyclase activator forskolin on steady-state and transient currents generated by the Na⁺-K⁺ pump were studied in guinea-pig ventricular myocytes by means of whole-cell voltage clamp at 30 °C.

2. In external solution containing 144 mM Na⁺ (Na⁺_o) and 10 mM K⁺ (K⁺_o), steady-state Na⁺-K⁺ pump current (I_p) activated by 5 mM pipette Na⁺ (Na⁺_pip) at -20 mV was reversibly augmented by forskolin (4 µM) to 133 ± 4 % of the control current (n = 15). The forskolin analogue 1,9-dideoxyforskolin (10 µM), which does not activate adenylyl cyclases, did not increase I_p (n = 2). Application of the protein kinase A (PKA) inhibitor H-89 (10 µM) in the continued presence of forskolin reversed the forskolin-induced elevation of I_p (n = 3).

3. The forskolin effect on I_p persisted in the presence of 50 mM Na⁺_pip which ensured that the internal Na⁺-binding sites of the Na⁺-K⁺ pump were nearly saturated. Under these conditions, the drug increased I_p to 142 ± 3 % of the control I_p when the pipette free Ca²⁺ concentration ([Ca²⁺]_pip) was 0·013 nM (n = 5) and to 138 ± 4 % of the control I_p when free [Ca²⁺]_pip was 15 nM (n = 9).

4. In Na⁺-free external solution, I_p activated by 50 mM Na⁺_pip and 1·5 mM K⁺_o was likewise increased by forskolin but to a lesser extent than in Na⁺-containing medium (116 ± 3 % of control, n = 10).

5. In order to investigate exclusively partial reactions in the Na⁺ limb of the pump cycle, transient pump currents under conditions of electroneutral Na⁺-Na⁺ exchange were studied. Transient pump currents elicited by voltage jumps displayed an initial peak and then decayed monoexponentially. Moved charge (Q) and the rate constant of current decay varied with membrane potential (V). The Q-V relationship followed a Boltzmann distribution characterized by the midpoint voltage (V_0·5) and the maximum amount of movable charge (Q_max). Forskolin (2-10 µM) shifted V_0·5 to more negative values while Q_max was not affected (n = 11). The effects of forskolin on transient pump currents were mimicked by 8-bromo-cAMP (500 µM; n = 2) and abolished by a peptide inhibitor of PKA (PKI, 10 µM; n = 5).

6. We conclude that activation of the cAMP-PKA pathway in guinea-pig ventricular myocytes increases Na⁺-K⁺ pump current at least in part by modulating partial reactions in the Na⁺ limb of the pump cycle. Under physiological conditions, the observed stimulation of the cardiac Na⁺-K⁺ pump may serve to shorten the action potential duration and to counteract the increased passive sarcolemmal Na⁺ and K⁺ fluxes during sympathetic stimulation of the heart.

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