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

Content Provider	PubMed Central
Author	Jens, Kockskämper Simone, Erlenkamp Glitsch, Helfried G.
Copyright Year	2000
Abstract	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. 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). 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). 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). 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 (ΔQ max). Forskolin (2-10 μM) shifted V 0·5 to more negative values while ΔQ 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). 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.
Related Links	http://dx.doi.org/10.1111/j.1469-7793.2000.t01-2-00561.x
Ending Page	574
Page Count	14
Starting Page	561
File Format	PDF
ISSN	00223751
e-ISSN	14697793
Journal	The Journal of Physiology
Issue Number	Pt 3
Volume Number	523
Language	English
Publisher	Blackwell Science Inc
Publisher Date	2000-03-01
Access Restriction	Open
Rights Holder	Blackwell Science Inc
Subject Keyword	Physiology Research in Higher Education
Content Type	Text
Resource Type	Article
Subject	Physiology Sports Science

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Steady-state current-voltage relationship of the Na/K pump in guinea pig ventricular myocytes

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

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