Channel-like functions of the 18-kDa translocator protein (TSPO): regulation of apoptosis and steroidogenesis as part of the host-defense response.
Channel-like functions of the 18-kDa translocator protein (TSPO): regulation of apoptosis and steroidogenesis as part of the host-defense response.
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DOI：
10.2174/138161207781368710
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发表时间：
2007-07
影响因子：
3.1
通讯作者：
L. Veenman;V. Papadopoulos;M. Gavish
中科院分区：
文献类型：
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作者：
L. Veenman;V. Papadopoulos;M. Gavish
由于其通道样特性，外周型苯二氮卓受体 (PBR) 已更名为易位蛋白 (TSPO)。在真核生物中，TSPO 主要位于线粒体外膜。在原核生物中，它存在于细胞膜中。 TSPO 具有广泛的功能，包括各种宿主防御反应、发育过程和线粒体功能。在本综述中，我们重点关注 TSPO 在免疫反应、细胞凋亡和类固醇生成中的作用，以确定这些功能是否可能受到包括 TSPO 在内的共同点的控制。在生理浓度（nM 范围）下，TSPO 特异性配体 PK 11195 和 Ro5-4864 似乎具有抗凋亡作用。据报道，通过基因操作敲低 TSPO，导致 [(3)H]PK 11195 结合减少 50% 以上，显示出抗凋亡作用，表明 TSPO 具有潜在的促凋亡功能。然而，发现 TSPO 丰度减少 70% 以上会导致细胞死亡，这可能是由于其他基本细胞功能受损所致。 TSPO的促凋亡功能可能涉及对线粒体电压依赖性阴离子通道（VDAC）和腺嘌呤核苷酸转运蛋白（ANT）形成的通道[即线粒体通透性转换孔（MPTP）]的调节。经常报道的 PK 11195 和 Ro5-4864 的促凋亡作用可能是由于这些特定 TSPO 配体的低亲和力结合位点所致，与 VDAC 和 ANT 没有直接关系。同样，在 nM 范围内的浓度下，PK 11195 和 Ro5-4864 似乎可以刺激类固醇生成。对于此功能，TSPO 本身似乎就足够了，即不涉及 VDAC 和 ANT。 TSPO 似乎作为转运蛋白/通道将胆固醇转移到线粒体中，在线粒体中胆固醇转化为孕烯醇酮，孕烯醇酮是进一步类固醇生成的前体。细胞凋亡和类固醇在宿主防御反应的各个方面发挥着重要作用。因此，我们的综述表明，TSPO 及其配体参与免疫反应、细胞凋亡和类固醇生成等看似不同的生物学功能，可能在 TSPO 在宿主对疾病和损伤的防御反应中的多维作用中具有共同点。
Due to its channel-like properties, the peripheral-type benzodiazepine receptor (PBR) has been renamed the translocator protein (TSPO). In eukaryotes, the TSPO is primarily located in the outer mitochondrial membrane. In prokaryotes, it is found in the cell membrane. A broad spectrum of functions has been attributed to the TSPO, including various host defense responses, developmental processes, and mitochondrial functions. In the present review, we focus on the role of TSPO in immunological responses, apoptosis, and steroidogenesis, to determine whether these functions may be governed by a common denominator including TSPO. At physiological concentrations (nM range), the TSPO specific ligands, PK 11195 and Ro5-4864, appear to be anti-apoptotic. Knockdown of TSPO by genetic manipulation, resulting a reduction by more than 50% in [(3)H]PK 11195 binding, was reported to show anti-apoptotic effects, suggesting a potential pro-apoptotic function of TSPO. However, a reduction of more than 70% of TSPO abundance was found to cause cell death, possibly due to impairment of other essential cell functions. The pro-apoptotic function of TSPO may involve the modulation of the channel formed by the mitochondrial voltage-dependent anion channel (VDAC) and the adenine nucleotide transporter (ANT) [i.e., the mitochondrial permeability transition pore (MPTP)]. The frequently reported pro-apoptotic effects of PK 11195 and Ro5-4864 may be due to sites with low-affinity binding for these specific TSPO ligands, and not directly related to VDAC and ANT. Also at concentrations in the nM range, PK 11195 and Ro5-4864 appear to stimulate steroidogenesis. For this function TSPO by itself appears to suffice i.e. no involvement of VDAC and ANT. TSPO appears to operate as a translocator/channel to transfer cholesterol into mitochondria where it is converted to pregnenolone, a precursor of further steroidogenesis. Apoptosis and steroids play important roles in various aspects of the host defense response. Thus, our review suggests that the involvement of TSPO and its ligands in such seemingly disparate biological functions as immunological responses, apoptosis, and steroidogenesis may have a common denominator in the multi-dimensional role of TSPO in the host-defense response to disease and injury.