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首页> 外文期刊>Toxins >Three Peptide Modulators of the Human Voltage-Gated Sodium Channel 1.7, an Important Analgesic Target, from the Venom of an Australian Tarantula
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Three Peptide Modulators of the Human Voltage-Gated Sodium Channel 1.7, an Important Analgesic Target, from the Venom of an Australian Tarantula

机译:来自澳大利亚狼蛛毒液的人电压门控钠通道1.7(重要的止痛目标)的三种肽调节剂

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Voltage-gated sodium (NaV) channels are responsible for propagating action potentials in excitable cells. NaV1.7 plays a crucial role in the human pain signalling pathway and it is an important therapeutic target for treatment of chronic pain. Numerous spider venom peptides have been shown to modulate the activity of NaV channels and these peptides represent a rich source of research tools and therapeutic lead molecules. The aim of this study was to determine the diversity of NaV1.7-active peptides in the venom of an Australian Phlogius sp. tarantula and to characterise their potency and subtype selectivity. We isolated three novel peptides, μ-TRTX-Phlo1a, -Phlo1b and -Phlo2a, that inhibit human NaV1.7 (hNaV1.7). Phlo1a and Phlo1b are 35-residue peptides that differ by one amino acid and belong in NaSpTx family 2. The partial sequence of Phlo2a revealed extensive similarity with ProTx-II from NaSpTx family 3. Phlo1a and Phlo1b inhibit hNaV1.7 with IC50 values of 459 and 360 nM, respectively, with only minor inhibitory activity on rat NaV1.2 and hNaV1.5. Although similarly potent at hNaV1.7 (IC50 333 nM), Phlo2a was less selective, as it also potently inhibited rNaV1.2 and hNaV1.5. All three peptides cause a depolarising shift in the voltage-dependence of hNaV1.7 activation.
机译:电压门控钠(Na V )通道负责在可兴奋细胞中传播动作电位。 Na V 1.7在人类疼痛信号通路中起着至关重要的作用,并且是治疗慢性疼痛的重要治疗靶点。已显示许多蜘蛛毒液肽可调节Na 通道的活性,这些肽代表了丰富的研究工具和治疗先导分子来源。这项研究的目的是确定在澳大利亚Phlogius sp。的毒液中Na V 1.7-活性肽的多样性。狼蛛并描述其效力和亚型选择性。我们分离了三种抑制人Na V 1.7(hNa V 1.7)的新型肽μ-TRTX-Phlo1a,-Phlo1b和-Phlo2a。 Phlo1a和Phlo1b是35个残基的肽,相差一个氨基酸,属于NaSpTx家族2。部分Phlo2a与NaSpTx家族3的ProTx-II具有广泛的相似性。Phlo1a和Phlo1b抑制hNa V 1.7,IC 50 值分别为459和360 nM,对大鼠Na V 1.2和hNa V 1.5的抑制作用较小。尽管在hNa V 1.7(IC 50 333 nM)具有相似的效力,但Phlo2a的选择性较低,因为它也有效抑制rNa V 1.2和hNa V 1.5。这三种肽均引起hNa V 1.7激活的电压依赖性的去极化移位。

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