Comparative analysis of the effects of synthetic derivatives of batrachotoxin on sodium currents in frog node of Ranvier

Bi, Khodorov; Yelin, E. A.; Zaborovskaya, L. D.; Maksudov, Movljan Z.; Tikhomirova, O. B.; Leonov, Vladimir N.

doi:10.1007/bf00711639

Cited by 11 publications

(6 citation statements)

References 18 publications

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“…The pyrrole ring is essential for BTX activity (54,55). In the horseshoe binding model, the pyrrole ring approaches Ser 1i15 , and the BTX carbonyl oxygen is within H-bonding distance from the amide group of Asn 2i15 .…”

Section: Discussionmentioning

confidence: 99%

Identification of New Batrachotoxin-sensing Residues in Segment IIIS6 of the Sodium Channel

Garden

Wang

et al. 2011

Journal of Biological Chemistry

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Ion permeation through voltage-gated sodium channels is modulated by various drugs and toxins. The atomistic mechanisms of action of many toxins are poorly understood. A steroidal alkaloid batrachotoxin (BTX) causes persistent channel activation by inhibiting inactivation and shifting the voltage dependence of activation to more negative potentials. Traditionally, BTX is considered to bind at the channel-lipid interface and allosterically modulate the ion permeation. However, amino acid residues critical for BTX action are found in the inner helices of all four repeats, suggesting that BTX binds in the pore. In the octapeptide segment IFGSFFTL in IIIS6 of a cockroach sodium channel BgNa V , besides Ser_3i15 and Leu_3i19, which correspond to known BTX-sensing residues of mammalian sodium channels, we found that Gly_3i14 and Phe_3i16 are critical for BTX action. Using these data along with published data as distance constraints, we docked BTX in the Kv1.2-based homology model of the open BgNa V channel. We arrived at a model in which BTX adopts a horseshoe conformation with the horseshoe plane normal to the pore axis. The BTX ammonium group is engaged in cation-interactions with Phe_3i16 and BTX moieties interact with known BTX-sensing residues in all four repeats. Oxygen atoms at the horseshoe inner surface constitute a transient binding site for permeating cations, whereas the bulky BTX molecule would resist the pore closure, thus causing persistent channel activation. Our study reinforces the concept that steroidal sodium channel agonists bind in the inner pore of sodium channels and elaborates the atomistic mechanism of BTX action.Voltage-gated sodium channels (Na V ) are responsible for the rapid rising phase of the action potential in nerve and muscle cells. The pore-forming ␣-subunit of Na V channels contains four repeats, and each repeat has six transmembrane helices (S1-S6). The S1-S4 helices form the voltage sensor domain.Positively charged S4 helices move outward in response to membrane depolarization. The S5 and S6 helices contribute to the pore-forming domain. The extracellular linkers connecting S5 and S6 helices form the four re-entrant P-loops, which contain the selectivity filter residues. In the absence of x-ray structures of Na V channels, their homology models, which are based on x-ray structures of potassium channels, are used to explain structure-activity relationships of various sodium channel ligands, including local anesthetics (1-4), steroidal activators (5-8), and pyrethroid insecticides (9, 10). Recent reinterpretation of data on substituted cysteine accessibility of the Ca V 2.1 channel (11) in view of a the channel homology model, which is based on the x-ray structure of the open voltage-gated potassium channel Kv1.2 (12), further supports a general similarity of the inner pore architecture in different voltage-gated cationic channels (13).Sodium channels are targets for numerous drugs and naturally occurring toxins. Batrachotoxin (BTX) 4 is a steroidal sodium-channel agonist, which...

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Section: Discussionmentioning

confidence: 99%

Identification of New Batrachotoxin-sensing Residues in Segment IIIS6 of the Sodium Channel

Garden

Wang

et al. 2011

Journal of Biological Chemistry

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“…1). Since the aromatic ring is necessary for activity [23,24], we docked the activators with the initial orientation of the aromatic ring towards the selectivity filter.…”

Section: Models Of Na+ Channel With Ligandsmentioning

confidence: 99%

Sodium channel activators: Model of binding inside the pore and a possible mechanism of action

Tikhonov

Zhorov

2005

FEBS Letters

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Sodium channel activators, batrachotoxin and veratridine, cause sodium channels to activate easier and stay open longer than normal channels. Traditionally, this was explained by an allosteric mechanism. However, increasing evidence suggests that activators can bind inside the pore. Here, we model the open sodium channel with activators and propose a novel mechanism of their action. The activator-bound channel retains a hydrophilic pathway for ions between the ligand and conserved asparagine in segment S6 of repeat II. One end of the activator approaches the selectivity filter, decreasing the channel conductance and selectivity. The opposite end reaches the gate stabilizing it in the open state.

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“…Studies with semi-synthetic BTX derivatives demonstrate that removal of the C20-ester results in compounds that lose considerable potency (Figure S9. 37 Reduction of the B-ring double bond in BTX affords a toxin derivative that hyperpolarizes V1/2, but no longer completely blocks inactivation. Synthetic analogues of the AB-ring of BTX containing pendant amine groups antagonize BTX binding, but do not hyperpolarize V1/2 or eliminate inactivation.…”

Section: Discussionmentioning

confidence: 99%

Differential Effects of Modified Batrachotoxins on Voltage-gated Sodium Channel Fast and Slow Inactivation

MacKenzie¹,

Abderemane-Ali²,

Garrison³

et al. 2021

Preprint

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Voltage-gated sodium channels (NaVs), large transmembrane protein complexes responsible for the initiation and propagation of action potentials, are targets for a number of acute poisons. Many of these agents act as allosteric modulators of channel activity and serve as powerful chemical tools for understanding channel function. Batrachotoxin (BTX) is a steroidal amine derivative most commonly associated with poison dart frogs and is unique as a NaV ligand in that it alters every property of the channel, including threshold potential of activation, inactivation, ion selectivity, and ion conduction. Structure-function studies with BTX are limited, however, by the inability to access preparative quantities of this compound from natural sources. We have addressed this problem through de novo synthesis of BTX, which gives access to modified toxin structures. In this report, we detail electrophysiology studies of three BTX C20-ester derivatives against recombinant NaV subtypes (rat NaV1.4 and human NaV1.5). Two of these compounds, BTX-B and BTX-cHx, are functionally equivalent to BTX, hyperpolarizing channel activation and blocking both fast and slow inactivation. BTX-yne—a C20-n-heptynoate ester—is a conspicuous outlier, eliminating fast but not slow inactivation. This unique property qualifies BTX-yne as the first reported NaV modulator that separates inactivation processes. These findings are supported by functional studies with bacterial NaVs (BacNaVs) that lack a fast inactivation gate. The availability of BTX-yne should advance future efforts aimed at understanding NaV gating mechanisms and designing allosteric regulators of NaV activity.

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Comparative analysis of the effects of synthetic derivatives of batrachotoxin on sodium currents in frog node of Ranvier

Cited by 11 publications

References 18 publications

Identification of New Batrachotoxin-sensing Residues in Segment IIIS6 of the Sodium Channel

Identification of New Batrachotoxin-sensing Residues in Segment IIIS6 of the Sodium Channel

Sodium channel activators: Model of binding inside the pore and a possible mechanism of action

Differential Effects of Modified Batrachotoxins on Voltage-gated Sodium Channel Fast and Slow Inactivation

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