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

Gadsby, David C.; Nakao, Masakazu

doi:10.1085/jgp.94.3.511

Cited by 205 publications

(176 citation statements)

References 58 publications

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“…7 A, but with bath application of 0.5 mM ouabain in the maintained external presence of 20 mM K + and 140 mM Na +. Ouabain block of the Na+/K + pump (Gadsby and Nakao, 1989) caused significant activation of KAC h. Again, the effect was due to changes in the frequency of opening rather than mean open time. Block of the Na+/K + pump caused KACh activation indistinguishable from that by Na +.…”

Section: Block Of the Na+ /K + Pump Activates Kac Hmentioning

confidence: 93%

Na+ activation of the muscarinic K+ channel by a G-protein-independent mechanism.

Sui

Chan

Logothetis

1996

The Journal of General Physiology

123

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Muscarinic potassium channels (KAch) are composed of two subunits, GIRK1 and GIRK4 (or CIR), and are directly gated by G proteins. We have identified a novel gating mechanism of KAC h, independent of G-protein activation. This mechanism involved functional modification of KACh which required hydrolysis of physiological levels of intracellular ATP and was manifested by an increase in the channel mean open time. The ATP-modifled channels could in turn be gated by intracellular Na +, starting at ~3 mM with an ECs0 of ~40 raM. The Na+-gating of KAC h was operative both in native atrial cells and in a heterologous system expressing recombinant channel subunits. Block of the Na+/K + pump (e.g., by cardiac glycosides) caused significant activation of KAC h in atrial cells, with a time course similar to that of Na + accumulation and in a manner indistinguishable from that of Na+-mediated activation of the channel, suggesting that cardiac glycosides activated KACh by increasing intracellular Na + levels. These results demonstrate for the first time a direct effect of cardiac glycosides on atrial myocytes involving ion channels which are critical in the regulation of cardiac rhythm.

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Section: Block Of the Na+ /K + Pump Activates Kac Hmentioning

confidence: 93%

Na+ activation of the muscarinic K+ channel by a G-protein-independent mechanism.

Sui

Chan

Logothetis

1996

The Journal of General Physiology

123

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“…K + channel currents were minimized by omitting K + from both intra-and extracellular solutions, and including 20 mM TEA + in pipette solutions. Omission of external K + and internal Na + also prevented currents generated by the Na+/K + pump (Gadsby and Nakao, 1989). Na+/Ca 2+ exchange current (Kimura, Noma, and Irisawa, 1986) was prevented by lack of internal Na + and internal and external Ca 2÷.…”

Section: Whole-cell Current Recordingmentioning

confidence: 94%

Functionally distinct phospho-forms underlie incremental activation of protein kinase-regulated Cl- conductance in mammalian heart.

Hwang

Horie

Gadsby

1993

The Journal of General Physiology

Self Cite

107

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The regulation of cardiac CI-conductance by cAMP-dependent protein kinase (PKA) and cellular phosphatases was studied in isolated guinea pig ventricular myocytes by using wide-tipped, perfused pipettes to record whole-cell currents. Exposure to forskolin (Fsk) or isoproterenol (Iso) elicits a CI-conductance that results exclusively from PKA-dependent phosphorylation because it can be completely abolished, or its activation fully prevented, by switching to pipette solution containing PKI, a synthetic peptide inhibitor of PKA. The CI-conductance activated by micromolar concentrations of either agonist reached its steady-state amplitude in 1-2 min and was deactivated promptly and entirely, usually within 2 min, upon washing out the agonist, implying a continuous high level of activity of endogenous protein phosphatases. Accordingly, intraceUular application of okadaic acid or microcystin, both potent inhibitors of protein phosphatases 1 and 2A, during exposure to Fsk enhanced the steady-state CI-conductance and slowed its deactivation after washing out the Fsk. Maximal potentiation of the conductance, by ~ 60%, was obtained with pipette concentrations of ~ 10 I~M okadaic acid (or ~ 5 ~tM microcystin) and did not result from an increase in the apparent affirfity for Fsk. In the presence of maximally effective concentrations of okadaic acid and/or microcystin, deactivation of the enhanced CI-conductance upon washout of agonist was incomplete, with about half of the conductance persisting indefinitely. That residual conductance did not reflect continued action of PKA because it was insensitive to PKI, but was identified as a fraction of the activated CI-conductance by its biophysical characteristics. The results suggest that complete deactivation of the PKA-regulated cardiac CI-conductance requires dephosphorylation by a type 1 and/or 2A phosphatase, but that partial deactivation can be accomplished by activity of some other phosphatase(s). These findings are' consistent with sequential phosphorylation of a protein, probably the CI-channel itself, at two different kinds

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“…The increase in the rate of membrane depolarization-i.e., a faster rate of membrane charging toward firing threshold-was apparently caused by the inward current induced by blocking the sodium pump with strophanthidin (Wang and Huang 2004). Because the inward current is present at a wide range of potentials with very negative reversal potentials (see Gadsby and Nakao 1989;Glitsch 2001;Glitsch and Tappe 1995), for quantitative purposes, we simply defined the rate of membrane depolarization as the slope of a straight line drawn between the peak AHP and the threshold. In this case, the rate was increased from 0.32 to 0.62 mV/ms (Fig.…”

Section: Strophanthidin Effectsmentioning

confidence: 99%

Effects of Sodium Pump Activity on Spontaneous Firing in Neurons of the Rat Suprachiasmatic Nucleus

Wang¹,

Huang²

2006

Journal of Neurophysiology

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. Effects of sodium pump activity on spontaneous firing in neurons of the rat suprachiasmatic nucleus. J Neurophysiol 96: 109 -118, 2006. First published February 8, 2006 doi:10.1152/jn.01369.2005. Cell-attached and whole cell recording techniques were used to study the effects of electrogenic sodium pump on the excitability of rat suprachiasmatic nucleus (SCN) neurons. Blocking the sodium pump with the cardiac steroid strophanthidin or zero K ϩ increased the spontaneous firing of SCN neurons to different degrees with different recording modes, whereas turning the sodium pump into a nonselective cation channel with the marine toxin palytoxin invariably increased the spontaneous firing to the point of total blockade. Current-clamp recordings indicated that strophanthidin increased the rate of membrane depolarization and reduced the peak afterhyperpolarization potential (AHP), whereas zero K ϩ also increased the rate of depolarization, but enhanced the peak AHP. The dual effect of zero K ϩ was reflected by the biphasic time course of voltage responses to zero K ϩ : an inhibitory phase with enhanced peak AHP and slower firing, followed by a delayed excitatory phase with faster rate of membrane depolarization and faster firing. In the presence of strophanthidin to block the sodium pump, zero K ϩ consistently decreased firing by enhancing the peak AHP. Repetitive applications of K ϩ -free solution gradually turned the biphasic inhibitory-followed-by-excitatory voltage response into a monophasic inhibitory response in cells recorded with the whole cell (but not the cell-attached) mode, suggesting rundown of sodium pump activity. Taken together, the results suggest that spontaneous firing of SCN neurons is regulated by sodium pump activity as well as the AHP, and that sodium pump activity is modulated by intracellular soluble substances subject to rundown under the whole cell conditions.

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

Cited by 205 publications

References 58 publications

Na+ activation of the muscarinic K+ channel by a G-protein-independent mechanism.

Na+ activation of the muscarinic K+ channel by a G-protein-independent mechanism.

Functionally distinct phospho-forms underlie incremental activation of protein kinase-regulated Cl- conductance in mammalian heart.

Effects of Sodium Pump Activity on Spontaneous Firing in Neurons of the Rat Suprachiasmatic Nucleus

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