Antillatoxin is a sodium channel activator that displays unique efficacy in heterologously expressed rNav1.2, rNav1.4 and rNav1.5 α subunits.
Antillatoxin is a sodium channel activator that displays unique efficacy in heterologously expressed rNav1.2, rNav1.4 and rNav1.5 α subunits.
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Antillatoxin是一种钠通道激活剂，在异源表达的RNAV1.2，RNAV1.4和RNAV1.5α亚基中显示出独特的功效。
DOI：
10.1186/1471-2202-11-154
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发表时间：
2010-12-14
期刊：
影响因子：
2.4
通讯作者：
Murray TF
中科院分区：
文献类型：
--
作者：
Cao Z;Gerwick WH;Murray TF
抗藻毒素（ATX）是由海洋蓝细菌巨大鞘丝藻（Lyngbya majuscula）产生的一种结构独特的脂肽。ATX在未定义的识别位点激活电压门控钠通道α亚基，并刺激神经元中的钠内流。然而，ATX对钠通道α-亚基的药理学性质和选择性尚未完全表征。在这项研究中，我们通过使用Na+选择性荧光染料，钠结合苯并呋喃三乙酸酯，表征了ATX在异源表达rNav1.2，rNav1.4或rNav1.5 α-亚基的细胞中的药理学性质和选择性。ATX在表达每个钠通道α-亚基的细胞中产生钠内流，而另外两种钠通道激活剂藜芦碱和短毒素-2则没有作用。rNav1.2、rNav1.4和rNav1.5的ATX效价无显著差异。同样，rNav1.2、rNav1.4和rNav1.5 α-亚基之间对ATX诱导的钠内流的疗效也无显著差异。在rNav1.4 α-亚基的钙渗透性DEAA突变体中，ATX相对于其他钠通道激活剂也产生了强大的Ca 2+内流。最后，我们证明了8-去甲基-8，9-二氢-抗拉毒素类似物在刺激钠内流方面的有效性和效力较低。ATX在刺激表达rNav1.2、rNav1.4和rNav1.5 α-亚基的细胞中的钠内流方面显示出独特的功效。ATX的功效是独特的，因为它不被VGSC α亚基上的神经毒素位点2和5的激活剂共享。鉴于ATX与钠通道α-亚基相互作用的独特药理学性质，解码抗拉毒素的分子决定因素和作用机制可能会进一步深入了解钠通道门控机制。
Antillatoxin (ATX) is a structurally unique lipopeptide produced by the marine cyanobacterium Lyngbya majuscula. ATX activates voltage-gated sodium channel α-subunits at an undefined recognition site and stimulates sodium influx in neurons. However, the pharmacological properties and selectivity of ATX on the sodium channel α-subunits were not fully characterized. In this study, we characterized the pharmacological properties and selectivity of ATX in cells heterologously expressing rNav1.2, rNav1.4 or rNav1.5 α-subunits by using the Na+ selective fluorescent dye, sodium-binding benzofuran isophthalate. ATX produced sodium influx in cells expressing each sodium channel α-subunit, whereas two other sodium channel activators, veratridine and brevetoxin-2, were without effect. The ATX potency at rNav1.2, rNav1.4 and rNav1.5 did not differ significantly. Similarly, there were no significant differences in the efficacy for ATX-induced sodium influx between rNav1.2, rNav1.4 and rNav1.5 α-subunits. ATX also produced robust Ca2+ influx relative to other sodium channel activators in the calcium-permeable DEAA mutant of rNav1.4 α-subunit. Finally, we demonstrated that the 8-demethyl-8,9-dihydro-antillatoxin analog was less efficacious and less potent in stimulating sodium influx. ATX displayed a unique efficacy with respect to stimulation of sodium influx in cells expressing rNav1.2, rNav1.4 and rNav1.5 α-subunits. The efficacy of ATX was distinctive inasmuch as it was not shared by activators of neurotoxin sites 2 and 5 on VGSC α-subunits. Given the unique pharmacological properties of ATX interaction with sodium channel α-subunits, decoding the molecular determinants and mechanism of action of antillatoxin may provide further insight into sodium channel gating mechanisms.
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