KATP channels confer survival advantage in cocaine overdose.
KATP channels confer survival advantage in cocaine overdose.
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KATP 通道在可卡因过量时具有生存优势。
DOI：
10.1038/sj.mp.4002083
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发表时间：
2007
影响因子：
11
通讯作者：
Terzic,A
中科院分区：
文献类型：
--
作者：
Reyes,S;Kane,GC;Miki,T;Seino,S;Terzic,A
在这个国家，可卡因的使用影响了3千多万人，并且造成了大多数因吸毒过量而死亡的人。虽然人们对可卡因毒性的药效学越来越了解，但决定致命结果的分子决定因素在很大程度上仍然未知。的确，在可卡因中毒中，主要的管理是支持性的，主要限于镇静和监测生命体征。2在这里，我们报道对可卡因引起的死亡的易感性是遗传控制的。通过确定KCNJ11基因作为可卡因过量反应的保护元件，本研究揭示了以前未被认识到的可卡因中毒靶向治疗框架。交感神经系统的过度激活导致需求和供应的不匹配，从而产生癫痫发作、心律紊乱和心肺衰竭，这是可卡因毒性的既定基础。通过抑制突触前神经元对儿茶酚胺的再摄取，可卡因诱导交感神经递质的过度积累，导致肾上腺素能亢进的普遍状态。分布于全身的atp敏感的Kþ （KATP）通道最近被认为与确保对交感神经激增所施加的全身应激的耐受性有关。KATP通道作为独特的分子变阻器，能够调节膜电位依赖性功能以适应细胞代谢需求。强调KATP通道在重要的稳态功能中的关键作用，靶向破坏KCNJ11，编码成孔的Kir6基因。2个KATP通道亚基，诱发全面性癫痫，心力衰竭和应激下心律失常。因此，我们在这里测试了KATP通道功能是否在可卡因毒性的情况下提供了保护机制。由于全身注射了有毒剂量的可卡因，Kir6。2-knockout (Kir6。与性别和年龄匹配的野生型（WT）对照相比，2-KO小鼠7 - 9表现出明显的生存劣势（图1a）。具体来说，在24小时的随访中，单次注射可卡因（100mgkgÀ1 ip）在Kir6中产生67%的死亡率。2-KO （n= 15）与WT中15%的死亡率相比（n= 14， P< 0.01；图1a）。事实上，Kir6中功能性KATP通道的缺失。2-基因缺陷的人群倾向于迅速和大规模的死亡，在Kir6中也观察到这种倾向于WT加重死亡率。反复滥用可卡因后2-KO （P= 0.008, WT vs Kir6）。2-KO;图1 b)。因此，完整的KATP通道的存在对可卡因过量的存活至关重要。尽管KATP通道提供了保护，但WT小鼠对可卡因表现出明显的脆弱性（图1a和b）。在WT中通过预处理促进KATP通道活性
Cocaine use affects more than 30 million people in this country, and is responsible for the majority of deaths ascribed to drug overdose. 1 While the pharmacodynamics of cocaine toxicity are increasingly understood, the molecular determinants that define fatal outcome remain largely unknown. Indeed, in cocaine poisoning the mainstay of management is supportive, limited predominantly to sedation and monitoring of vital signs. 2 Here, we report that the susceptibility to cocaine-induced mortality is genetically controlled. By identifying the KCNJ11 gene as a safeguard element in the response to cocaine overdose, the present study unmasks a previously unrecognized framework for targeted therapy of cocaine intoxication. An overdriven activation of the sympathetic nervous system, which results in a mismatch of demand and supply producing seizures, heart rhythm disorders and cardiopulmonary collapse, is an established substrate of cocaine toxicity. 3 By inhibiting reuptake of catecholamines in presynaptic neurons, cocaine induces an excessive accumulation of sympathetic neurotransmitters, resulting in a general state of hyperadrenergic stimulation. 4 Distributed throughout the body, ATP-sensitive Kþ (KATP) channels have been recently implicated in securing tolerance to systemic stress imposed by a sympathetic surge. 5 KATP channels operate as unique molecular rheostats, capable of adjusting membrane potential-dependent functions to match cellular metabolic demands. 6 Underscoring the critical role for KATP channels in vital homeostatic functions, targeted disruption of KCNJ11, the gene encoding the pore-forming Kir6. 2 subunit of KATP channels, precipitates generalized seizure, 7 heart failure8 and arrhythmia under stress. 9 Therefore, we tested here whether KATP channel function provides a protective mechanism in the setting of cocaine toxicity. In response to systemic administration of a toxic dose of cocaine, Kir6. 2-knockout (Kir6. 2-KO) mice7–9 demonstrated a marked survival disadvantage compared to sex-and age-matched wild-type (WT) controls (Figure 1a). Specifically, at 24-h follow-up, a single injection of cocaine (100mgkgÀ1 ip) produced a 67% mortality in the Kir6. 2-KO (n= 15) compared to 15% mortality in the WT (n= 14, P< 0.01; Figure 1a). In fact, the absence of functional KATP channels in the Kir6. 2-deficient cohort predisposed to a prompt and massive lethality, with this propensity to aggravated mortality over WT also observed in the Kir6. 2-KO following repeated cocaine abuse (P= 0.008, WT vs Kir6. 2-KO; Figure 1b). Thus, the presence of intact KATP channels critically defines survivorship in cocaine overdose. Despite protection afforded by KATP channels, WT mice demonstrated a significant vulnerability to cocaine (Figures 1a and b). Promotion of KATP channel activity in the WT through pretreatment with