Three Peptide Modulators of the Human Voltage-Gated Sodium Channel 1.7, an Important Analgesic Target, from the Venom of an Australian Tarantula.
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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DOI：
10.3390/toxins7072494
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发表时间：
2015-06-30
期刊：
影响因子：
4.2
通讯作者：
Rash LD
中科院分区：
文献类型：
--
作者：
Chow CY;Cristofori-Armstrong B;Undheim EA;King GF;Rash LD
电压门控钠（NaV）通道负责在可兴奋细胞中传播动作电位。NaV1.7在人类疼痛信号通路中起着至关重要的作用，是治疗慢性疼痛的重要治疗靶点。许多蜘蛛毒液肽已被证明可以调节NaV通道的活性，这些肽代表了研究工具和治疗先导分子的丰富来源。本研究的目的是确定的多样性的NaV1.7活性肽的毒液中的澳大利亚Phlogius sp.狼蛛，并验证其效力和亚型的选择性。我们分离了三个新的肽，μ-TRTX-Phlo 1a，-Phlo 1b和-Phlo 2a，抑制人NaV1.7（hNaV1.7）。Phlo 1a和Phlo 1b是35个残基的肽，它们相差一个氨基酸，属于NaSpTx家族2。Phlo 2a的部分序列显示与NaSpTx家族3的ProTx-II具有广泛的相似性。Phlo 1a和Phlo 1b抑制hNaV1.7，IC 50值分别为459和360 nM，对大鼠NaV1.2和hNaV1.5仅有轻微抑制活性。尽管Phlo 2a对hNaV1.7具有类似的抑制作用（IC 50 333 nM），但其选择性较低，因为它也能有效抑制rNaV1.2和hNaV1.5。所有三种肽引起hNaV1.7激活的电压依赖性的去极化转变。
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.