Doxapram, K2p通道阻滞剂和pH对心率的影响:幼虫果蝇模型

Elizabeth R. Elliott, Alaina C. Taul, Maya O. Abul-Khoudoud, Nicole Hensley, R. Cooper
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摘要

两个p域K+ (K2p)通道负责维持静息膜电位。K2p通道在健康组织中有不同的表达,但在癌变或病变状态下也会发生变化。K2p通道表达变化的相关性和原因仍在研究中。化合物doxapram似乎阻断了K2p通道并使细胞去极化。以果蝇为研究对象,研究了心肌和骨骼肌中ORK1 - K2p通道表达的增加。果蝇幼虫的心率对pH值非常敏感,由于多巴胺阻断了已知对酸敏感的K2p通道的一个子集,因此假设多巴胺会影响心率。pH值从7.1到6.5增加了反应速率,而从7.1到7.5则降低了反应速率。0.1 mM的doxapram没有效果,但0.5 mM的doxapram在5分钟内降低了果蝇的心率。暴露于5毫米的多巴胺会立即降低这一比率。来自革兰氏阴性菌的脂多糖(lps)急剧增加了这一比率。脂多糖激活幼体骨骼肌中的K2p通道,并被多巴胺阻断。脂多糖能轻微降低多巴胺诱导的抑郁率。心脏和骨骼肌中K2p通道的过度表达降低心率,提高pH敏感性。在幼体神经肌肉连接处,骨骼肌中的过表达增加了自发量子事件的频率,并产生更负的静息膜电位。
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Effect of Doxapram, a K2p Channel Blocker, and pH on Heart Rate: Larval Drosophila Model
Two-P-domain K+ (K2p) channels are responsible for maintaining the resting membrane potential. K2p channels have varied expression in healthy tissue, but they also change in cancerous or diseased states. The correlation and causation as regards the alteration of K2p channel expression are still being investigated. The compound doxapram seems to block K2p channels and depolarize cells. Using Drosophila, the increased expression of the ORK1 K2p channel in cardiac and skeletal muscle was investigated. The heart rate in larval Drosophila is very sensitive to pH, and since doxapram blocks a subset of the K2p channels that are known to be acid-sensitive, it was postulated that doxapram would affect heart rate. A pH change from 7.1 to 6.5 increased the rate, while that from 7.1 to 7.5 decreased the rate. An amount of 0.1 mM of doxapram had no effect, but 0.5 of mM depressed Drosophila heart rates within five minutes. Exposure to 5 mM of doxapram immediately decreased the rate. Lipopolysaccharides (LPSs) from Gram-negative bacteria acutely increased the rate. LPSs activate K2p channels in the skeletal muscle of larvae and are blocked by doxapram. LPSs slightly reduce depression in the rate induced by doxapram. The overexpression of K2p channels in the heart and skeletal muscle depressed the heart rate and heightened pH sensitivity. At larval neuromuscular junctions, the overexpression in skeletal muscle increases the frequency of spontaneous quantal events and produces a more negative resting membrane potential.
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