APETx2, A Kind of ASIC3 Channel Blocker

2018-10-09

Introduction 

APETx2, a 42 amino-acid peptide toxin isolated from sea anemone Anthopleura elegantissima, is a kind of acid-sensing ion channel 3 (ASIC3) channel blocker (IC50 values are 63 and 175 nM for homomeric rat and human ASIC3 channels). It also inhibits NaV1.8 and NaV1.2 channels (IC50 values are 55 and 114 nM, respectively). Besides, it demonstrates analgesic properties against acid-induced and inflammatory pain.

Pharmacologic action

APETx2 is a basic peptide (pI = 9.59) of 42 amino acids, crosslinked by three disulfide bridges, similar to PcTX1. However, it does not show any sequence homologies with PcTX1. It has a calculated
280nm molecular absorbance of ε280 = 11170. The full sequence of APETx2 was established by N-terminal Edman degradation
and its measured monoisotopic mass (4557.96Da) was perfect in accordance with the mass calculated from sequence
data (4557.88Da, accuracy 17.5ppm), suggesting a free C-terminal carboxylic acid. APETx2 does not modify the triggering or kinetics of the action potential in rat sensory neurons, thus demonstrating no nonspecific effect on voltage-dependent Na+ channels, although APETx2 has sequence homologies with the Anthopleura sp. toxins (AP-A, AP-B, AP-C), which are potent activators of voltage-dependent Na+ channels.

Function

APETx2 is a selective and potent inhibitor for homomeric ASIC3 and ASIC3 containing channels. It reduces transient peak acid-evoked currents mediated by homomeric ASIC3 channels in primary cultures of sensory neurons and in heterologous expression systems. On the contrary, the sustained component of the ASIC3 current is insensitive to APETx2. APETx2 inhibits heteromeric ASIC3/1a (IC50 = 2 mM), ASIC3/1b (IC50 = 900 nM), and ASIC3/ 2b (IC50 = 117 nM), in addition to homomeric ASIC3 channels (IC50 = 63 nM for rat and 175 nM for human). Besides, the homomeric ASIC1a, ASIC2a, ASIC1b, and heteromeric ASIC3/2a channels are not sensitive to APETx2.

Pharmacokinetics and metabolism

To evaluate the toxicity and/or possible behavioral changes, the central injections of APETx2 in mice were administered. The experimental results showed that the intracisternal injections of 5, 10, and 20mg of APETx2 did not induce neurotoxic symptoms in mice even after 24 h. And the behavior of injected mice was same as that of control mice which was injected with physiological solution.

References:

S. Diochot, A. Baron, L. D. Rash, E. Deval, P. Escoubas, S. Scarzello and M. Lazdunski. A new sea anemone peptide, APETx2, inhibits ASIC3, a major acid‐sensitive channel in sensory neurons. EMBO J., 2004, 23(7), 1516-1525.

Z. G. Xiong, G. Pignataro, M. Li, S. Y. Chang and R. P. Simon. Acid-sensing ion channels (ASICs) as pharmacological targets for neurodegenerative diseases. Curr. Opin. Pharmacol., 2008, (1), 25-32.

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