APETx2 is a peptide toxin derived from Anthopleura elegantissimaand serves as a selective, reversible inhibitor of the acid-sensing ion channel 3 (ASIC3)[1-2]. By inhibiting the activity of the ASIC3 channel, APETx2 blocks acid-induced pain signaling. APETx2 can be used in research related to inflammatory pain, post-infectious irritable bowel syndrome, and gastric mucosal injury[3-4].
In vitro, rat articular chondrocytes were pretreated with APETx2 (3µM) and PcTx1 (100ng/ml) for 1 hour, followed by incubation under acidic conditions (pH=6.0) for 3 hours. APETx2 significantly alleviated acidosis-induced cytotoxicity and apoptosis, exerting a chondroprotective effect by reducing intracellular Ca²⁺ levels and inhibiting the phosphorylation of the p38/ERK1/2 MAPK signaling pathway[5]. Under magnesium-free medium conditions (used to induce epileptiform discharge), primary hippocampal neurons were incubated with APETx2 (63nM) for 1 hour. APETx2 significantly increased the frequency of burst discharges induced by the magnesium-free medium[6].
In vivo, APETx2 (20pmol per mouse) was injected into the Zusanli acupoint (ST36) of a fibromyalgia mouse model. By antagonizing ASIC3, APETx2 significantly reduced mechanical hyperalgesia on day 14 post-induction and decreased the overexpression of pain-related channel proteins ASIC3, Nav1.7, and Nav1.8 in the dorsal root ganglia, spinal cord, and thalamus[7]. In a rat model of osteoarthritis, daily continuous intra-articular injections of APETx2 (2.5µg/kg) for 7 days, APETx2 significantly inhibited weight-bearing asymmetry and secondary mechanical hyperalgesia in the knee joint. APETx2 also effectively prevented articular cartilage damage by reducing chondrocyte loss and matrix destruction[8].
References:
[1] Yuan L, Xiao H, Li H, et al. APETx2 regulates intestinal motility and visceral sensitivity in post-infectious irritable bowel syndrome mice through 5-HT signalling pathway. J Pharm Pharmacol. 2023 Apr 17;75(5):712-717.
[2] Li J, Wei Y, Wang Y, et al. Metabolomics study of APETx2 post-conditioning on myocardial ischemia-reperfusion injury. Front Pharmacol. 2024 Dec 6;15:1470142.
[3] Diochot S, Baron A, Rash LD, et al. A new sea anemone peptide, APETx2, inhibits ASIC3, a major acid-sensitive channel in sensory neurons. EMBO J. 2004 Apr 7;23(7):1516-25.
[4] Chagot B, Escoubas P, Diochot S, et al. Solution structure of APETx2, a specific peptide inhibitor of ASIC3 proton-gated channels. Protein Sci. 2005 Aug;14(8):2003-10.
[5] Zhou RP, Ni WL, Dai BB, et al. ASIC2a overexpression enhances the protective effect of PcTx1 and APETx2 against acidosis-induced articular chondrocyte apoptosis and cytotoxicity. Gene. 2018 Feb 5;642:230-240.
[6] Cao Q, Xiao ZM, Wang X, et al. Inhibition of Acid Sensing Ion Channel 3 Aggravates Seizures by Regulating NMDAR Function. Neurochem Res. 2018 Jun;43(6):1227-1241.
[7] Yen LT, Hsieh CL, Hsu HC, et al. Preventing the induction of acid saline-induced fibromyalgia pain in mice by electroacupuncture or APETx2 injection. Acupunct Med. 2020 Jun;38(3):188-193.
[8] Izumi M, Ikeuchi M, Ji Q, et al. Local ASIC3 modulates pain and disease progression in a rat model of osteoarthritis. J Biomed Sci. 2012 Aug 21;19(1):77.
APETx2是一种来自Anthopleura elegantissima的肽毒素，是选择性、可逆的酸敏感离子通道3（ASIC3）抑制剂[1-2]。APETx2通过抑制ASIC3通道的活性，以阻断酸诱导的疼痛信号传导。APETx2可用于炎症性疼痛、感染后肠易激综合征和胃黏膜损伤的相关研究[3-4]。
在体外，APETx2（3µM）及PcTx1（100ng/ml）预处理大鼠关节软骨细胞1小时，随后在酸性（pH=6.0）条件下培养3小时。APETx2能显著减轻酸化诱导的细胞毒性与凋亡，并通过降低细胞内Ca²⁺水平及抑制p38/ERK1/2/MAPK信号通路磷酸化，发挥软骨保护作用[5]。在不含Mg²⁺的培养基（用于诱导癫痫样放电）的条件下，APETx2（63nM孵育）海马神经元细胞1小时，APETx2显著增强了由无镁培养基诱导的爆发性放电频率[6]。
在体内，向纤维肌痛小鼠模型的足三里穴（ST36）注射APETx2（20pmol/只），APETx2通过拮抗酸性离子通道3（ASIC3），显著减轻了诱导后第14天的机械性痛觉过敏，并降低了背根神经节、脊髓和丘脑中与疼痛相关的ASIC3、Nav1.7和Nav1.8通道蛋白的过表达[7]。在骨关节炎模型大鼠膝关节中，每日连续注射APETx2（2.5μg/kg），持续7天，APETx2显著抑制了膝关节的负重分布不对称性以及继发性机械性痛觉过敏。APETx2还通过减少关节软骨细胞丢失和基质破坏，有效防止了关节软骨损伤[8]。