Small K channels: big targets for treating alcoholism?
Small K channels: big targets for treating alcoholism?
复制标题
小K通道：治疗酗酒的大目标？
DOI：
10.1016/j.biopsych.2011.01.016
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发表时间：
2011
影响因子：
10.6
通讯作者：
Harris,RAdron
中科院分区：
文献类型：
--
作者：
Morikawa,Hitoshi;Harris,RAdron
Alcohol abuse and alcoholism represent major health problems in Western countries and are emerging as major concerns in many developing countries. Despite the large social and economic impact of excessive alcohol consumption, treatment options, particularly pharmacotherapies, are limited. This is, in part, due to a lack of a detailed understanding of the targets of alcohol action in brain that might be responsible for promoting excessive alcohol consumption. Accumulating evidence in recent years indicates important roles for calcium (Ca2+)-activated potassium (K+) channels in behavioral responses to alcohol and the development of alcoholism (1). In this issue of Biological Psychiatry, two articles propose that small-conductance Ca2+-activated K+(SK) channels may be novel therapeutic targets for alcohol dependence and excessive drinking associated with alcoholism (refs to the two papers here). Among ion channels expressed in the plasma membrane, SK channels are unique in that they are solely activated, or gated, by cytosolic Ca2+ and not directly by membrane potential (2). Thus, Ca2+ influx through Ca2+-permeable ion channels, such as NMDA-type glutamate receptors or voltage-gated Ca2+ channels, elicits SK channel opening, resulting in negative feedback regulation of excitatory glutamatergic transmission and action potential firing (Figure 1).In the first study, Mulholland et al. examined changes in SK channel function and expression following chronic ethanol exposure in the cornu ammonis 1 (CA1) region of the hippocampus, a brain area that is thought to be involved in withdrawal-induced seizures and in cognitive impairments observed in alcoholics. In CA1 pyramidal neurons, SK2 subtype SK channels are localized to dendritic spines, where they are tightly coupled to synaptically driven Ca2+ influx via NMDA receptors or voltage-gated Ca2+ channels (3). This synaptic activation of SK2 channels constitutes a Ca2+-mediated negative feedback loop to dampen excitatory postsynaptic potentials (EPSPs) and spine Ca2+ signals that are critical for the induction of synaptic plasticity and glutamate-induced neurotoxicity. Indeed, blocking SK channels with the specific antagonist apamin facilitates hippocampal synaptic plasticity in brain slices and hippocampus-dependent memory encoding in behaving animals (2). Using organotypic slice preparations from Sprague Dawley rat pups, Mulholland et al. first show that chronic ethanol treatment (75 mmol/L for 7–9 days) results in 1) reduced SK channel function, assessed by measuring the apamin-sensitive component of depolarization-induced outward currents or that of glutamatergic EPSPs, in CA1 pyramidal neurons, and 2)
