Heteropoda toxin 2 is a gating modifier toxin specific for voltage-gated K+ channels of the Kv4 family

Zarayskiy, Vladislav; Balasubramanian, Ganesh; Bondarenko, Vladimir E.; Morales, Michael J.

doi:10.1016/j.toxicon.2004.11.015

Cited by 39 publications

(47 citation statements)

References 46 publications

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“…It was suggested that this was due to selective expression of Kv1.4 channels in these DRG neurons and their inhibition by 4-AP. However, the conclusion that Kv1.4 would be the sole contributor to firing in DRG neurons is inconsistent with our findings that HPTx, a Kv4 channel blocker (Zarayskiy, 2005), also induced tonic firing in C-R phasic DRG neurons. The Kv4 family of K + channels is also widely expressed in DRG neurons (Winkelman et al, 2005).…”

Section: Discussioncontrasting

confidence: 99%

“…Heteropodatoxin II (HPTx, 0.05 μM, Fig. 2AB), a blocker of low threshold inactivating K + currents (Kv4) (Zarayskiy et al, 2005), mimicked the effects of SP in phasic neurons significantly increasing the number of APs (from 1.2/600ms to 10/600ms, n=4) elicited by a prolonged depolarizing current pulse. Similarly, low concentrations of 4-aminopyridine (4-AP, 50 μM, Fig.…”

Section: Resultsmentioning

confidence: 98%

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Neurokinins enhance excitability in capsaicin-responsive DRG neurons

Sculptoreanu

Groat

2007

Experimental Neurology

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Neurokinins released by capsaicin-responsive (C-R) dorsal root ganglia neurons (DRG) may control firing in these neurons by an autofeedback mechanism. Here we used patch clamp techniques to examine the effects of neurokinins on firing properties of dissociated DRG neurons of male rats. In C-R neurons that generated only a few action potentials (APs, termed phasic) in response to long depolarizing current pulses (600 ms), substance P (SP, 0.5 μM) lowered the AP threshold by 11.0 ±0.3 mV and increased firing from 1.1±0.7 APs to 5.2±0.6 APs. In C-R tonic neurons that fire multiple APs, SP elicited smaller changes in AP threshold (6.0±0.1 mV reduction) and the number of APs (11±1 vs. 9±1 in control). The effects of SP were similar to the effect of heteropodatoxin II (0.05 μM) or low concentrations of 4-aminopyridine (50 μM) that block A-type K + currents. A selective NK 2 agonist, [βAla 8 ]-neurokinin A (4-10) (0.5 μM), mimicked the effects of SP. The effects of SP in C-R phasic neurons were fully reversed by an NK 2 receptor antagonist (MEN10376, 0.5 μM) but only partially by a protein kinase C (PKC) inhibitor (bisindolylmaleimide, 0.5 μM). An NK 3 selective agonist ([MePhe 7 ]-neurokinin B, 0.5 μM), an NK 1 selective agonist ([Sar 9 , Met 11 ]-substance P, 0.5 μM) or activation of PKC with phorbol 12, 13-dibutyrate (0.5 μM) did not change firing. Our data suggest that the excitability of C-R phasic afferent neurons is increased by activation of NK 2 receptors and intracellular signaling mediated only in part by PKC.

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Section: Discussioncontrasting

confidence: 99%

Section: Resultsmentioning

confidence: 98%

Neurokinins enhance excitability in capsaicin-responsive DRG neurons

Sculptoreanu

Groat

2007

Experimental Neurology

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“…Both in vivo data and our studies using heterologously expressed channels have strongly suggested that HpTx2 is specific for Kv4 channels (Zarayskiy et al, 2005). HpTx2 inhibition of Kv4.3 was voltage-dependent, shifting the threshold for activation to more depolarized potentials, speeding deactivation, and slowing inactivation (Zarayskiy et al, 2005). Alanine scanning mutagenesis showed that HpTx2 interacts with two amino acids in the S3b TMS of the VSD (DeSimone et al, 2009).…”

Section: Introductionmentioning

confidence: 69%

“…In contrast to Kv4.3, the HpTx2-induced gating modification of Kv4.1 was much less voltage-dependent (Zarayskiy et al, 2005). This surprising observation led us to compare the interaction between HpTx2 and these two channels.…”

Section: Introductionmentioning

confidence: 95%

“…It is one of more than 300 known ion-channel peptide toxins that form an "inhibitor cysteine knot" (ICK) motif, most of which have been identified in spider venom (Gracy et al, 2008). Both in vivo data and our studies using heterologously expressed channels have strongly suggested that HpTx2 is specific for Kv4 channels (Zarayskiy et al, 2005). HpTx2 inhibition of Kv4.3 was voltage-dependent, shifting the threshold for activation to more depolarized potentials, speeding deactivation, and slowing inactivation (Zarayskiy et al, 2005).…”

Section: Introductionmentioning

confidence: 98%

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Heteropoda Toxin 2 Interaction with Kv4.3 and Kv4.1 Reveals Differences in Gating Modification

DeSimone

Zarayskiy²,

Bondarenko³

et al. 2011

Mol Pharmacol

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Kv4 (Shal) potassium channels are responsible for the transient outward K ϩ currents in mammalian hearts and central nervous systems. Heteropoda toxin 2 (HpTx2) is an inhibitor cysteine knot peptide toxin specific for Kv4 channels that inhibits gating of Kv4.3 in the voltage-dependent manner typical for this type of toxin. HpTx2 interacts with four independent binding sites containing two conserved hydrophobic amino acids in the S3b transmembrane segments of Kv4.3 and the closely related Kv4.1. Despite these similarities, HpTx2 interaction with Kv4.1 is considerably less voltage-dependent, has smaller shifts in the voltage-dependences of conductance and steady-state inactivation, and a 3-fold higher K d value. Swapping four nonconserved amino acids in S3b between the two channels exchanges the phenotypic response to HpTx2. To understand these differences in gating modification, we constructed Markov models of Kv4.3 and Kv4.1 activation gating in the presence of HpTx2. Both models feature a series of voltagedependent steps leading to a final voltage-independent transition to the open state and closely replicate the experimental data. Interaction with HpTx2 increases the energy barrier for channel opening by slowing activation and accelerating deactivation. The greater degree of voltage-dependence in Kv4.3 occurs because it is the voltage-dependent transitions that are most affected by HpTx2; in contrast, it is the voltage-independent step in Kv4.1 that is most affected by the presence of toxin. These data demonstrate the basis for subtype-specificity of HpTx2 and point the way to a general model of gating modifier toxin interaction with voltage-gated ion channels.

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Dissection of the voltage-activated potassium outward currents in adult mouse ventricular myocytes: I to,f, I to,s, I K,slow1, I K,slow2, and I ss

et al. 2011

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Voltage-activated outward K(+) currents (I (Kv)) are essential for cardiac repolarization and are major factors in the electrophysiological remodeling and arrhythmias seen in heart disease. Mouse models have been useful for understanding cardiac electrophysiology. However, previous methods for separating and quantifying the components of I (Kv) in mouse myocardium have yielded inconsistencies. In this study, we developed a statistically rigorous method to uniquely quantify various I (Kv) in adult mouse ventricular myocytes, and concluded that tri-exponential functions combined with depolarizing pulses of duration greater than 20 s are essential to adequately separate the different I (Kv) components. This method enabled us to reliably dissect the kinetic components of the decay phase of I (Kv) into fast (I (to)), intermediate (K(V)1.5-encoded I (K,slow1)) and slow (K(V)2-encoded I (K,slow2)) components. The most rapid kinetic phase, I (to), can be further dissected into fast (K(V)4-encoded I (to,f)) and slow (K(V)1.4-encoded I (to,s)) components by measuring recovery from inactivation, voltage-dependence of activation and sensitivity to HpTx-2 and 4-AP. The applicability of our dissection method was validated using transgenic mice over-expressing dominant-negative K(V)1.1 transgene which largely abolished the 4-AP-sensitive portion of I (to) (i.e., I (to,s)) and the I (K,slow1) component. We also applied our method to Irx5-deficient mice and verified selective elevations of I (to) in endocardial myocytes. Our method should prove useful in future electrophysiological studies using mouse.

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Heteropoda toxin 2 is a gating modifier toxin specific for voltage-gated K+ channels of the Kv4 family

Cited by 39 publications

References 46 publications

Neurokinins enhance excitability in capsaicin-responsive DRG neurons

Neurokinins enhance excitability in capsaicin-responsive DRG neurons

Heteropoda Toxin 2 Interaction with Kv4.3 and Kv4.1 Reveals Differences in Gating Modification

Dissection of the voltage-activated potassium outward currents in adult mouse ventricular myocytes: I to,f, I to,s, I K,slow1, I K,slow2, and I ss

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