Kinetic analysis of single sodium channels from canine cardiac Purkinje cells.

Scanley, B. Ellen; Hanck, Dorothy A.; Chay, Teresa Ree; Fozzard, Harry A.

doi:10.1085/jgp.95.3.411

Cited by 80 publications

(84 citation statements)

References 38 publications

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“…The tivate directly from closed states without opening (35,36). If lidocaine block is somehow augmented by closed-state inactivation, then enhanced lidocaine block of the R1623Q mutant could develop rapidly during depolarization.…”

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confidence: 99%

A revised view of cardiac sodium channel “blockade” in the long-QT syndrome

Kambouris¹,

Nuss²,

Johns³

et al. 2000

J. Clin. Invest.

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Mutations in SCN5A, encoding the cardiac sodium (Na) channel, are linked to a form of the congenital long-QT syndrome (LQT3) that provokes lethal ventricular arrhythmias. These autosomal dominant mutations disrupt Na channel function, inhibiting channel inactivation, thereby causing a sustained ionic current that delays cardiac repolarization. Sodium channel-blocking antiarrhythmics, such as lidocaine, potently inhibit this pathologic Na current (I Na ) and are being evaluated in patients with LQT3. The mechanism underlying this effect is unknown, although high-affinity "block" of the open Na channel pore has been proposed. Here we report that a recently identified LQT3 mutation (R1623Q) imparts unusual lidocaine sensitivity to the Na channel that is attributable to its altered functional behavior. Studies of lidocaine on individual R1623Q single-channel openings indicate that the open-time distribution is not changed, indicating the drug does not block the open pore as proposed previously. Rather, the mutant channels have a propensity to inactivate without ever opening ("closed-state inactivation"), and lidocaine augments this gating behavior. An allosteric gating model incorporating closed-state inactivation recapitulates the effects of lidocaine on pathologic I Na . These findings explain the unusual drug sensitivity of R1623Q and provide a general and unanticipated mechanism for understanding how Na channel-blocking agents may suppress the pathologic, sustained Na current induced by LQT3 mutations. Japanese girl who had the long-QT syndrome and who was effectively treated with mexiletine, a lidocaine analogue (21). Heterologous expression of human heart Na channels (hH1) with R1623Q revealed destabilized inactivation from the open state (22, 23) consistent with the important role of the domain IV-S4 charge sensor in inactivation gating (24,25). In addition, it appeared that this disrupted inactivation phenotype, in analogy to the other LQT3 disorders, was at least partly corrected by lidocaine (22).Here we report that the R1623Q Na channel is unusually sensitive to lidocaine. Surprisingly, we find that lidocaine neither plugs the open channel, nor repairs the inactivation of open channels as proposed previously (22). Rather, our findings reveal an unanticipated mechanism for lidocaine action. We find that lidocaine augments an intrinsic inactivation gating process that is amplified in R1623Q, known as closed-state inactivation, and thereby prevents channel opening altogether. Our results reveal a molecular mechanism for the unusual lidocaine sensitivity of this particular mutant, while implicating closed-state inactivation as an important functional therapeutic target for Na channel-blocking agents in other long QT disorders. MethodsSite-directed mutagenesis of residue R1623 in the hH1 Na channel α subunit was performed using standard methods (26) and was sequence verified. For expression in Xenopus oocytes, α-subunit cRNAs were coinjected with an equimolar ratio of β 1 subunit cRNA as described previously (...

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mentioning

confidence: 99%

A revised view of cardiac sodium channel “blockade” in the long-QT syndrome

Kambouris¹,

Nuss²,

Johns³

et al. 2000

J. Clin. Invest.

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“…Experimentally a clear rising phase was described in the first latency histogram of cardiac Na+ channels and was attributed to the presence of multiple closed states (Grant, Starmer & Strauss, 1983;Kunze et al 1985;Scanley et al 1990). However, the data in the early time after the changing potential have not been quantitatively analysed because of the uncertainty due to the duration of the capacity transient (Grant et al 1983;Scanley et al 1990). …”

Section: Resultsmentioning

confidence: 99%

“…the mean lifetime cannot solely be attributed to a single rate constant. Yue et al (1989) However, different values have also been reported, most probably depending on a variety of models used for analysis; an e-fold change per 11 mV in canine ventricular cells (Berman et al 1989) using the approach of Aldrich, Corey & Stevens (1983), or an e-fold change per 30 + 4 mV by fitting data to five states in the Markovian model (Scanley et al 1990). …”

Section: Resultsmentioning

confidence: 99%

“…In canine Purkinje cells, an e-fold change per 30 + 6 mV was obtained (Scanley et al 1990). The former value may be more straightforward than the latter.…”

Section: Resultsmentioning

confidence: 99%

“…it did not allow for a qualitative determination of the activation kinetics. Furthermore, recent single channel studies have suggested that the time course of inactivation of the macroscopic Na' current attributes much to activation kinetics (Berman, Camardo, Robinson & Siegelbaum, 1989; Yue, Lawrence & Marban, 1989;Scanley. Hanck, Chay & Fozzard, 1990).…”

Section: Introductionmentioning

confidence: 99%

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Quantification of exponential Na+ current activation in N‐bromoacetamide‐treated cardiac myocytes of guinea‐pig.

Mitsuiye

Noma

1993

The Journal of Physiology

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SUMMARY1. The activation kinetics of the Na+ current was investigated in single ventricular cells of the guinea-pig heart using an improved oil-gap voltage clamp method. The inactivation of the current was removed by an intracellular application of Nbromoacetamide (NBA) for less than 1 min. Although the NBA treatment slightly decreased the peak amplitudes (817 + 13'4 % of control, n = 15), the Na+ current remained stable after the removal of inactivation.2. On depolarization, the activation of Na+ current took an exponential time course after the capacitive current decreased to 5 % of its peak amplitude (40-100 jts after the pulse onset). The time course of deactivation, recorded on repolarization from 1'2 ms depolarization, was also a single exponential.3. The time constants of activation and deactivation were almost identical when compared at a given test potential within a range of -50 to -30 mV. These findings indicate that the cardiac Na+ current activation is determined by m' kinetics, or one rate-limiting step.4. At potentials negative to -60 mV, the deactivation was complete, and its time constant decreased e-fold per 20-3 + 1-8 mV hyperpolarization (n = 7).5. The degree of steady-state activation (m(oo)) was fitted to a Boltzmann equation with a slope factor of 7-4 + 0-3 mV and a half-maximum potential of -33-3+0 8 mV (n = 8).6

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The late sodium current in heart failure: pathophysiology and clinical relevance

Horváth

Bers

2014

ESC Heart Failure

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Large and growing body of data suggest that an increased late sodium current (I Na,late ) can have a significant pathophysiological role in heart failure and other heart diseases. The first goal of this article is to describe how I Na,late functions under physiological circumstances. The second goal is to show the wide range of cellular mechanisms that can increase I Na,late in cardiac disease, and also to describe how the up-regulated I Na,late contributes to the pathophysiology of heart failure. The final section of the article discusses the possible use of I Na,late -modifying drugs in heart failure, on the basis of experimental and preclinical data.

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Kinetic analysis of single sodium channels from canine cardiac Purkinje cells.

Cited by 80 publications

References 38 publications

A revised view of cardiac sodium channel “blockade” in the long-QT syndrome

A revised view of cardiac sodium channel “blockade” in the long-QT syndrome

Quantification of exponential Na+ current activation in N‐bromoacetamide‐treated cardiac myocytes of guinea‐pig.

The late sodium current in heart failure: pathophysiology and clinical relevance

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