Acute lipopolysaccharide (LPS)-induced cell membrane hyperpolarization is independent of voltage gated and calcium activated potassium channels

IF 3.9 3区 环境科学与生态学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY Comparative Biochemistry and Physiology C-toxicology & Pharmacology Pub Date : 2024-08-16 DOI:10.1016/j.cbpc.2024.110004
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Abstract

The gram-negative toxin lipopolysaccharides (LPS) are known to trigger inflammatory cytokines in mammals, which can result in pathological responses. Upon treatment of bacterial sepsis with antibiotics, the lysing bacteria can present a surge in LPS, inducing a cytokine storm. However, LPS can also have direct cellular effects, including transient rapid hyperpolarizing of the membrane potential, blocking glutamate receptors and even promoting release of glutamate. The detailed mechanism of action for these immediate responses is still unresolved. In addressing the membrane hyperpolarization, voltage gated K+ channel blockers 4-aminopyridine (4-AP, 3 mM), quinidine hydrochloride monohydrate (0.1 mM) and tetraethylammonium (TEA, 20 mM) were examined along with RNAi knockdowns of potential calcium activated K+ channels. The immediate responses of LPS were not blocked. Even in the presence of glutamate, the membrane still hyperpolarizes with LPS. When the driving gradient for the ionotropic glutamate receptors is enhanced during hyperpolarization, spontaneous quantal responses are dampened in amplitude. Thus, glutamate receptors are blocked, and the mechanism of hyperpolarization remains unresolved. The larval Drosophila glutamatergic neuromuscular junction is used as a model synaptic preparation to address the direct rapid actions by LPS.

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急性脂多糖(LPS)诱导的细胞膜超极化与电压门控和钙激活钾通道无关。
众所周知,革兰氏阴性毒素脂多糖(LPS)会引发哺乳动物体内的炎症细胞因子,从而导致病理反应。用抗生素治疗细菌性败血症时,溶解的细菌会使 LPS 激增,诱发细胞因子风暴。不过,LPS 也能对细胞产生直接影响,包括一过性地迅速使膜电位超极化、阻断谷氨酸受体,甚至促进谷氨酸的释放。这些直接反应的详细作用机制仍未确定。为了解决膜超极化问题,研究人员研究了电压门控 K+ 通道阻断剂 4-氨基吡啶(4-AP,3 毫摩尔)、一水盐酸奎尼丁(0.1 毫摩尔)和四乙基铵(TEA,20 毫摩尔)以及潜在钙激活 K+ 通道的 RNAi 敲除。LPS 的直接反应没有被阻断。即使在谷氨酸存在的情况下,LPS 仍会使膜超极化。在超极化过程中,当离子型谷氨酸受体的驱动梯度增强时,自发量子反应的幅度会受到抑制。因此,谷氨酸受体被阻断,超极化的机制仍悬而未决。本研究以果蝇幼虫谷氨酸能神经肌肉接头为突触制备模型,探讨 LPS 的直接快速作用。
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来源期刊
CiteScore
7.50
自引率
5.10%
发文量
206
审稿时长
30 days
期刊介绍: Part C: Toxicology and Pharmacology. This journal is concerned with chemical and drug action at different levels of organization, biotransformation of xenobiotics, mechanisms of toxicity, including reactive oxygen species and carcinogenesis, endocrine disruptors, natural products chemistry, and signal transduction with a molecular approach to these fields.
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