A mechanistic interpretation of the action of toxin II from Anemonia sulcata on the cardiac sodium channel

Schultze-Seemann, Wolfgang; Kazerani, Helena; Tritthart, H. A.

doi:10.1016/0005-2736(87)90124-6

Cited by 37 publications

(23 citation statements)

References 21 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Similarly, 11.5 pS unitary conductance was reported for the ATX-II modified cardiac sodium (Schreibmayer et al, 1987). Subconductance current levels could occasionally be observed not only with the CHL-T and ATX-II modified channels, as previously described (Nagy, 1987d), but also with the SCT modified channels.…”

Section: Single-channel Current Amplitudessupporting

confidence: 83%

“…I have never observed such long openings. The discrepancy could be explained by the different patch configuration, the different temperature and perhaps a different filter frequency; McCarthy and Yeh (1987) worked with excised patches at 10~ whereas I used cell-attached patches at T -> 12~ ATX-II modified cardiac sodium channels also show bursting and an increased open time (Schreibmayer et al, 1987).…”

Section: Kinetic Properties Of the Modified Channelsmentioning

confidence: 99%

“…Although the effect of these substances on macroscopic inactivation is similar in different preparations, the effect on microscopic inactivation could be different. On the single-channel level, sea anemone toxin has been shown to prolong the channel open time and cause repetitive channel opening ("bursting") in cardiac muscle (Schreibmayer, Kazerani & Tritthart, 1987). In neuroblastoma cells it also causes bursts, but the channel open time is only moderately increased (Nagy, 1987d).…”

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Mechanism of inactivation of single sodium channels after modification by chloramine-T, sea anemone toxin and scorpion toxin

Nagy

1988

J. Membrain Biol.

View full text Add to dashboard Cite

Single sodium-channel currents were measured in neuroblastoma cells after inhibition of inactivation by chloramine-T (CHL-T), sea anemone toxin II (ATX-II) and scorpion toxin (SCT). The decaying phase of the averaged single-channel currents recorded with 90-msec pulses in cell-attached patches was clearly slower than that of the ummodified channels, suggesting inhibition of macroscopic inactivation. Each substance caused repetitive openings and a moderate increase in the channel open time. At Vm = RP + 20 mV and T = 12 degrees C, the mean channel open times were 1.4, 1.6 and 1.8 msec for CHL-T, ATX-II and SCT, respectively, as opposed to 1.07 msec for native channels. Open-time histograms could be best fitted by the sum of two exponentials. The time constants of the fits were similar for histograms constructed from single openings and from openings during bursts. This suggests that the population of channels is homogeneous and that in bursts the same open conformations of channels occur as in single openings. Mean burst durations for bursts consisting of more than one opening at Vm = RP + 20 mV were 4.9, 5.8 and 6.1 msec for CHL-T, ATX-II and SCT, respectively. Burst open-time histograms constructed from two or three openings were fitted by the gamma function. The different time constants of the fits obtained for ATX-II and SCT suggested multiple open conformations of channels for openings of bursts. However, significantly different open-time histograms constructed from the first, second and third openings of bursts could not be obtained systematically. A positive correlation was found for the dwell time of the first and the second, as well as for the second and the third opening of bursts with each substance, but a negative one for the dwell time of an opening and the neighboring closing of bursts with ATX-II. The results suggest a model with multiple open and inactivated states. In this model the inactivated states are weakly absorbing.

show abstract

Section: Single-channel Current Amplitudessupporting

confidence: 83%

Section: Kinetic Properties Of the Modified Channelsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Mechanism of inactivation of single sodium channels after modification by chloramine-T, sea anemone toxin and scorpion toxin

Nagy

1988

J. Membrain Biol.

View full text Add to dashboard Cite

show abstract

“…Site 3 sodium channel toxins have been suggested to slow the open state to inactivated state transition rate (Warashina and Fujita, 1983;Strichartz and Wang, 1986;Schreibmayer et al, 1987;Kirsch et al, 1989), but this phenomenon is difficult to study with macroscopic currents because current decay at a wide range of voltages represents a combination of delayed channel openings and channel inactivation (El-Sherif et al, 1992). Nevertheless, both the slowing of inactivation and the reduction in voltage dependence of steady-state inactivation observed in our experiments suggest that the general explanation proposed by Rogers et al (1996) regarding the putative mechanism of action of site 3 toxins is also applicable to BgII and BgIII: 1) the toxin receptor site undergoes a conformational change that is required for fast inactivation; 2) bound toxin slows this conformational change and, as a consequence, slows the inactivation process; and 3) since site 3 neurotoxins bound across the IVS3-S4 extracellular loop of the sodium channel and that translocation of IVS4 segment may be required for the inactivation gate to close, anemone toxins could be slowing or blocking such translocation and thus hindering inactivation.…”

Section: Discussionmentioning

confidence: 99%

The Sea Anemone Toxins BgII and BgIII Prolong the Inactivation Time Course of the Tetrodotoxin-Sensitive Sodium Current in Rat Dorsal Root Ganglion Neurons

Salceda¹,

Garateix²,

Soto³

2002

J Pharmacol Exp Ther

View full text Add to dashboard Cite

We have characterized the effects of BgII and BgIII, two sea anemone peptides with almost identical sequences (they only differ by a single amino acid), on neuronal sodium currents using the whole-cell patch-clamp technique. Neurons of dorsal root ganglia of Wistar rats (P5-9) in primary culture (LeibovitzЈs L15 medium; 37°C, 95% air/5% CO 2 ) were used for this study (n ϭ 154). These cells express two sodium current subtypes: tetrodotoxin-sensitive (TTX-S; K i ϭ 0.3 nM) and tetrodotoxinresistant (TTX-R; K i ϭ 100 M). Neither BgII nor BgIII had significant effects on TTX-R sodium current. Both BgII and BgIII produced a concentration-dependent slowing of the TTX-S sodium current inactivation (IC 50 ϭ 4.1 Ϯ 1.2 and 11.9 Ϯ 1.4 M, respectively), with no significant effects on activation time course or current peak amplitude. For comparison, the concentration-dependent action of Anemonia sulcata toxin II (ATX-II), a well characterized anemone toxin, on the TTX-S current was also studied. ATX-II also produced a slowing of the TTX-S sodium current inactivation, with an IC 50 value of 9.6 Ϯ 1.2 M indicating that BgII was 2.3 times more potent than ATX-II and 2.9 times more potent than BgIII in decreasing the inactivation time constant ( h ) of the sodium current in dorsal root ganglion neurons. The action of BgIII was voltage-dependent, with significant effects at voltages below Ϫ10 mV. Our results suggest that BgII and BgIII affect voltage-gated sodium channels in a similar fashion to other sea anemone toxins and ␣-scorpion toxins.

show abstract

“…Measuring currents that small is difficult and 10 nM ATX-II (anemonia sulcata toxin) was thus used to amplify the late sodium current. ATX-II has been proposed to enhance the late sodium current by prolonging the channel open time, facilitating channel opening from the closed state and preventing complete inactivation (Schreibmayer et al, 1987). In addition, ATX-II prolongs the APD and induces EADs in rabbit ventricular myocytes (Studenik et al, 2001).…”

Section: Currents In Isolated Cardiomyocytes (Papers III V)mentioning

confidence: 99%

Functional effects of the late sodium current inhibition by AZD7009 and lidocaine in rabbit isolated atrial and ventricular tissue and Purkinje fibre

Persson

Andersson

Duker

et al. 2007

European Journal of Pharmacology

View full text Add to dashboard Cite

Atrial fibrillation (AF) is the most common tachyarrhythmia in the adult population and is a major cause of morbidity and mortality. AF can be terminated and sinus rhythm restored by prolonging the action potential duration (APD) and the refractory period. Unfortunately, antiarrhythmic agents that prolong the APD and increase the refractory period via selective inhibition of the rapid delayed rectifier potassium current (IK r ), i.e. class III antiarrhythmic drugs, are associated with an increased risk of the ventricular tachycardia Torsades de Pointes. AZD7009 is an antiarrhythmic agent with predominant actions on atrial electrophysiology that shows high antiarrhythmic efficacy and low proarrhythmic potential in animals and man. The aim of the current studies was to characterize the effect of AZD7009 on cardiac ion currents and APD in order to provide a mechanistic explanation for its predominant atrial effects and low proarrhythmic potential.The human cardiac ion channels hERG (IK r ), Kv1.5 (IK ur ), Kv4.3/KChIP2.2 (I to ), KvLQT1/minK (IK s ), Kir3.1/Kir3.4 (IK ACh ) and Nav1.5 (INa) were expressed in mammalian cells. Whole-cell currents were inhibited by AZD7009 with the following IC 50 values: hERG 0.6 μM, Nav1.5 8 μM, Kv4.3/KChIP2.2 24 μM, Kv1.5 27 μM, Kir3.1/Kir3.4 166 μM and KvLQT1/minK 193 μM. Whole-cell sodium and calcium currents were recorded in isolated rabbit atrial and ventricular myocytes using amphotericin B perforated patch. The late sodium current in rabbit atrial and ventricular myocytes was inhibited by AZD7009 in a concentration dependent way, with approximately 50% inhibition at 10 μM AZD7009. The L-type Ca 2+ current (ICa L ) in rabbit ventricular myocytes was inhibited with an IC 50 of 90 μM. Transmembrane action potentials were recorded in tissue pieces from rabbit atrium, ventricle and Purkinje fibre in control, during exposure to the selective IK r blocker E-4031 and to E-4031 in combination with AZD7009. In Purkinje fibres, but not in ventricular tissue, AZD7009 attenuated the E-4031-induced APD prolongation. In contrast, in atrial cells, AZD7009 further prolonged the APD. In addition, AZD7009 was able to suppress early afterdepolarisations (EADs) induced by E-4031 in Purkinje fibre preparations.In conclusion, AZD7009 delays repolarisation and increases refractoriness in atrial tissue through synergistic inhibition of IK r , I to , IK ur and INa, a mixed ion channel blockade that may underlie its high antiarrhythmic efficacy. Inhibition of the late sodium current, counteracting excessive APD prolongation and EADs in susceptible cells (midmyocardial and Purkinje cells), may explain the low proarrhythmic potential of AZD7009.

show abstract

A mechanistic interpretation of the action of toxin II from Anemonia sulcata on the cardiac sodium channel

Cited by 37 publications

References 21 publications

Mechanism of inactivation of single sodium channels after modification by chloramine-T, sea anemone toxin and scorpion toxin

Mechanism of inactivation of single sodium channels after modification by chloramine-T, sea anemone toxin and scorpion toxin

The Sea Anemone Toxins BgII and BgIII Prolong the Inactivation Time Course of the Tetrodotoxin-Sensitive Sodium Current in Rat Dorsal Root Ganglion Neurons

Functional effects of the late sodium current inhibition by AZD7009 and lidocaine in rabbit isolated atrial and ventricular tissue and Purkinje fibre

Contact Info

Product

Resources

About