Brevetoxin-3 (PbTx-3) and its derivatives modulate single tetrodotoxin-sensitive sodium channels in rat sensory neurons.
Brevetoxin-3 (PbTx-3) and its derivatives modulate single tetrodotoxin-sensitive sodium channels in rat sensory neurons.
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发表时间：
1998-02
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通讯作者：
G. Jeglitsch;K. Rein;D. Baden;David John Adams
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作者：
G. Jeglitsch;K. Rein;D. Baden;David John Adams
Brevetoxin-3 (PbTx-3) 由海洋甲藻 (Ptychodiscus brevis) 产生，是一种亲脂性 11 环聚醚分子，以高亲和力与电压敏感钠 (Na+) 通道的位点 5 结合。通过膜片钳技术研究了细胞附着膜片中 PbTx-3 及其衍生物对从新生大鼠结状神经节分离的神经元的影响。 PbTx-3 (30-500 nM) 产生激活向更负膜电位的转变，从而在稳态条件下观察到单通道活性（维持去极化在-50 mV）。单一电流-电压关系是线性的，其反转电势约为+60 mV。在 PbTx-3 存在的情况下可以观察到两个单位电流幅度，斜率电导分别为 10.7 pS 和 21.2 pS。 PbTx-3 抑制 Na+ 通道的失活并延长这些通道的平均开放时间。添加到移液管溶液中的 1 µM 河豚毒素 (TTX) 可以阻断单一 Na+ 电流，这表明单通道电流是由 TTX 敏感的 Na+ 通道打开引起的。 PbTx-3 分子被认为具有多个与 Na+ 通道结合位点相互作用的活性中心（A 环内酯、R 侧链的 C-42）。在这些中心对 PbTx-3 的分子结构进行修饰产生了衍生物（PbTx-6、2,3,41,43-四氢-PbTx-3、2,3,27,28,41、43-六氢-PbTx-3 和 2,3-二氢-PbTx-3 A 环二醇），这些衍生物在对 Na+ 通道产生类似作用方面不如 PbTx-3 有效。动力学。 PbTx-3 及其衍生物可以深入了解电压敏感的 Na+ 通道门控机制。
Brevetoxin-3 (PbTx-3), produced by marine dinoflagellates (Ptychodiscus brevis), is a lipophilic 11-ring polyether molecule that binds with high affinity to site 5 of the voltage-sensitive sodium (Na+) channel. The effects of PbTx-3 and its derivatives were studied in cell-attached membrane patches on neurons dissociated from neonatal rat nodose ganglia by the patch-clamp technique. PbTx-3 (30-500 nM) produced a shift in activation to more negative membrane potentials whereby single-channel activity was observed under steady-state conditions (maintained depolarization at -50 mV). The unitary current-voltage relationship is linear, which exhibits a reversal potential of approximately +60 mV. Two unitary current amplitudes could be observed in the presence of PbTx-3, with slope conductances of 10.7 pS and 21.2 pS. PbTx-3 inhibits the inactivation of Na+ channels and prolongs the mean open time of these channels. Unitary Na+ currents could be blocked by 1 microM tetrodotoxin (TTX) added to the pipette solution, which indicates that the single-channel currents are caused by the opening of TTX-sensitive Na+ channels. The PbTx-3 molecule is proposed to have multiple active centers (A-ring lactone, C-42 of R side chain) interacting with the Na+ channel binding site. Modification of the molecular structure of PbTx-3 at these centers produced derivatives (PbTx-6, 2,3,41,43-tetrahydro-PbTx-3, 2,3,27,28,41, 43-hexahydro-PbTx-3 and 2,3-dihydro-PbTx-3 A-ring diol), which were less potent than PbTx-3 in producing similar effects on Na+ channel kinetics. PbTx-3 and its derivatives may provide insight into the mechanics of voltage-sensitive Na+ channel gating.