Potent blocker of voltage-gated sodium channels-Phrixotoxin 3

2018-10-09

Introduction 

The sodium channel subtypes NaV1.2 and NaV1.6 are the two major forms of excitatory pyramidal neurons in the cerebral cortex, with local specificity that can be combined with the initiation and spread of action potentials (APs). Voltage-gated sodium channels (VGSCs) are an important part of cellular function because they participate in the generation and propagation of action potentials. Studies have shown that PaurTx3 may be advanced from common ancestors through gene duplication to maintain a surface environment suitable for interaction with low voltage-dependent ion channels. Phrixotoxin 3 (PaurTx3), as one of the most potent peptide modulators in the voltage-gated sodium channel so far, with an IC50 value of 0.6±0.1 nM for Nav1.2,it is a white lyophilized solid with the molecular weight of 4059.74.

Pharmacologic action

Pharmacological inhibition of NaV1.2 by PaurTx3 suppresses FT-induced neuronal hyperexcitability in brain slice, while up-regulation of NaV1.2 as in NaV1.6 knockout mice showed an opposite effect. The PaurTx3 effectively inhibits the activation of wt rNav1.2a by interacting with the voltage sensor in domain II and it also can effectively block somatic sodium currents from neurons of both wildtype. PaurTx3 regulates voltage-gated sodium channels that are similar in nature to typical aerated modifier toxins, either to cause depolarization transfer of gated kinetics or to block the inward component of sodium current. PaurTx3 is particularly effective against Nav1.2 and is also the most potent toxin of Nav1.5 in recent study.

Function

After the injection of PaurTx3, the animal may develop a systemic ataxia immediately, with insufficient response to irritation and paralysis. After a few minutes, the mouse could not stand, and the breathing rhythm and strength were reduced. Symptoms gradually worsen, breathing gradually slowed down, unable to paralyze; died within 10-20 minutes after injection. The animals were completely in a state of relaxation, and during the poisoning process, there were no symptoms of excitotoxicity (sputum, convulsions, rapid movement).

References:

Seigo Ono, Tadashi Kimura and Tai Kubo. Characterization of voltage-dependent calcium channel blocking peptides from the venom of the tarantula Grammostola rosea. Toxicon, 2011, 58, 265–276.

Frank Bosmans, Lachlan Rash, Shunyi Zhu, Sylvie Diochot, Michel Lazdunski, Pierre Escoubas, and Jan Tytgat. Four Novel Tarantula Toxins as Selective Modulators of Voltage-Gated Sodium Channel Subtypes. Mol Pharmacol, 2006, 69, 419–429.

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