Facultad de Veterinaria, Departamento de Farmacología, Universidad de Santiago de Compostela, Lugo, Spain.
J Cell Biochem. 2010 May 15;110(2):497-508. doi: 10.1002/jcb.22566.
Gambierol is a marine polyether ladder toxin derived from the dinoflagellate Gambierdiscus toxicus. To date, gambierol has been reported to act either as a partial agonist or as an antagonist of sodium channels or as a blocker of voltage-dependent potassium channels. In this work, we examined the cellular effect of gambierol on cytosolic calcium concentration, membrane potential and sodium and potassium membrane currents in primary cultures of cerebellar granule cells. We found that at concentrations ranging from 0.1 to 30 microM, gambierol-evoked [Ca(2+)]c oscillations that were dependent on the presence of extracellular calcium, irreversible and highly synchronous. Gambierol-evoked [Ca(2+)]c oscillations were completely eliminated by the NMDA receptor antagonist APV and by riluzole and delayed by CNQX. In addition, the K(+) channel blocker 4-aminopyridine (4-AP)-evoked cytosolic calcium oscillations in this neuronal system that were blocked by APV and delayed in the presence of CNQX. Electrophysiological recordings indicated that gambierol caused membrane potential oscillations, decreased inward sodium current amplitude and decreased also outward IA and IK current amplitude. The results presented here point to a common mechanism of action for gambierol and 4-AP and indicate that gambierol-induced oscillations in cerebellar neurons are most likely secondary to a blocking action of the toxin on voltage-dependent potassium channels and hyperpolarization of sodium current activation.
吉宝醇是一种海洋聚醚梯型毒素，来源于有毒双鞭甲藻。迄今为止，吉宝醇已被报道为钠离子通道的部分激动剂或拮抗剂，或电压依赖性钾离子通道的阻断剂。在这项工作中，我们研究了吉宝醇对小脑颗粒细胞原代培养细胞内钙离子浓度、膜电位以及钠钾膜电流的细胞效应。我们发现，在 0.1 至 30μM 的浓度范围内，吉宝醇诱导的[Ca(2+)]c 振荡依赖于细胞外钙的存在，是不可逆的且高度同步的。NMDA 受体拮抗剂 APV、利鲁唑及 CNQX 可完全消除吉宝醇诱导的[Ca(2+)]c 振荡。此外，4-氨基吡啶（4-AP）可诱发该神经元系统内的细胞溶质钙离子振荡，该振荡可被 APV 阻断，并在 CNQX 存在时被延迟。电生理记录表明，吉宝醇引起膜电位振荡，降低内向钠电流幅度，也降低外向 IA 和 IK 电流幅度。这里呈现的结果指向吉宝醇和 4-AP 的共同作用机制，并表明吉宝醇诱导的小脑神经元振荡很可能是由于毒素对电压依赖性钾离子通道的阻断作用和钠电流激活的超极化所致。
