Batrachotoxin. The Active Principle of the Colombian Arrow Poison Frog, Phyllobates bicolor

Daly, J W; Witkop, Bernhard; Bommer, P; Biemann, K.

doi:10.1021/ja01079a026

Cited by 83 publications

(37 citation statements)

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“…Batrachotoxin (BTX) 4 is a steroidal sodium-channel agonist, which was first isolated from the skin of the Colombian frog Phyllobates bicolor (14). BTX binds preferentially to the open Na V channels (15)(16)(17) and alters several channel properties.…”

mentioning

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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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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“…10), isolated from the poison dart frog, Phyllobates terribilis, has been shown to activate sodium channels (Daly et al, 1965). It is apparent that the frog does not produce this compound and it is believed that it comes from a dietary insect source (http://library.thinkquest.org/C007974/ 2 _ 2poi.htm).…”

Section: Voltage-gated Ion Channelsmentioning

confidence: 99%

Analgesic substances derived from natural products (natureceuticals)

McCurdy

Scully

2005

Life Sciences

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“…The major venom of the Colombian poison arrow frog {Phyllobates aurotaenia) is batrachotoxin (VIb) (Märki and Witkop, 1963;Daly et al, 1965;Tokuyama et al, 1968Tokuyama et al, , 1969. The structure of homobatrachotoxin, formerly called isobatrachotoxin, is shown below (Vic).…”

Section: Steroidal Alkaloidsmentioning

confidence: 99%