温度敏感TRP离子通道的异源组装和功能研究
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摘要
温度感觉作为人体的一种重要感觉系统,对于感受周围环境变化,躲避危险性伤害以及维持机体内环境的稳定都具有非常重要的意义。长期以来对温度感觉机理的研究一直停留于直观描述阶段。造成温度感觉研究长期落后的主要原因在于温度感受器分子一直没有被确定。温度敏感TRP(Transient Receptor Potential)离子通道被分子克隆并证实为主要的细胞温度感受器,为在分子水平上研究温度感觉的分子机制提供了实验基础。
作者前期的研究工作表明温度敏感TRPV通道亚基间可以交互杂合组装为新的通道,杂合通道的类型和其不同的亚基配比有关,分子组装过程中亚基配比为随机的,杂合通道的电导和门控动力学特性介于纯合母体通道之间。通道亚基间的异源组装有助于离子通道在不同组织,不同细胞类型以及不同生理状态下功能多样性的广泛扩展。近年来对于温度敏感TRP通道的异源组装研究也有大量报道,但杂合通道的功能方面我们却知之甚少。
在本课题主要研究了杂合TRPV1/TRPV3通道在热、化合物及电位激活过程中的通道功能特性。同时作者还将通道异源组装的研究扩展到其它温度敏感TRP通道蛋白亚基。结果表明杂合TRPV1/TRPV3通道对TRPV1的激活剂和拮抗剂也都非常敏感;杂合TRPV1/TRPV3通道具有特定的温度敏感性、激活温度阈值和由热引发的通道敏化现象。杂合通道门控特性的改变显然是由TRPV1和TRPV3通道亚基间的相互作用所造成的。温度敏感TRP通道异源组装的实验研究中,作者证明了在细胞中表达TRPV1-TRPV3的串联体能够形成单一的杂合TRPV1/TRPV3通道,通过内面向外(inside-out)的膜片钳记录模式可以从表达串联体的细胞中记录到单通道电流。甚至单通道电导也很一致地处于纯合TRPV1和TRPV3通道的电导之间。这个结果和作者前期发表的有关TRPV1和TRPV3共同表达于细胞中可以组成杂合通道的结果一致。而对其它温度敏感TRP离子通道的异源组装研究显示其蛋白亚基间不能形成杂合通道。
综上所述,本研究证明了杂合TRPV1/TRPV3通道在细胞中的异源组装以及杂合通道在热激活及化学激活过程中功能的扩展,杂合通道的形成和功能特性的扩展也许有助于机体更加精确地对各种感觉和痛觉的敏感性进行细微的调节,从而更好地保护机体躲避有害刺激。
As one of the improtant sensory system, temperature reception involved sensing temperature changes to avoid the risk from environmental harm and to maintain the stability of the body. For a long time the mechanism of temperature reception has remained vague due to the molecular thermosensor had not been identified. Recently a group of cation channels referred to as ThermoTRPs by molecular cloning has been confirmed as the main cellular temperature sensors. The finding of temperature-sensitive TRP ion channels provides an experimental basis on the study of the mechanisms of temperature sensation on molecular level.
Previously we have demonstrated that co-expressing of TRPV1and TRPV3subunits yielded heteromeric channels with intermediate single-channel conductance and gating property. And the assembly between thermo-sensitive TRPV subunits appears to be random.
It is generally hypothesized that heteromeric assembly of TRPV channels underlies the molecular basis of fine-tuning of temperature sensation or chemical activation. However, very little is known about the functional properties of the heteromeric channels.In particular, how heteromeric TRPV1/TRPV3channels respond to heat and other stimuli remains unknown. Given the dramatic functional differences between TRPV1and TRPV3homomeric channels, it is of great interest to understand how heteromeric channels formed between them preserve the physiological properties of each subunit type and respond to benign or noxious stimuli.
In the present study, we investigated the functional properties of heteromeric TRPV1/TRPV3channel activated by voltage, chemicals and heat. We also extended our study to the assembly of other heteromeric Thermo-sensitive TRP channels.
Our results demonstrate that heteromeric TRPV1/TRPV3channels exhibit distinct temperature sensitivity, activation threshold, and heat-induced sensitization. Changes in gating properties apparently originate from interactions between TRPV1and TRPV3subunits. Thus, our results suggest that heteromeric TRPV1/TRPV3channels may serve as polymodal receptor for detecting tempertature changes and chemical irritants, especially noxicious stimuli.They may provide targets of novel therapeutic potentials for fine-tuning heat sensitivity as well as neuronal pain.
作者前期的研究工作表明温度敏感TRPV通道亚基间可以交互杂合组装为新的通道,杂合通道的类型和其不同的亚基配比有关,分子组装过程中亚基配比为随机的,杂合通道的电导和门控动力学特性介于纯合母体通道之间。通道亚基间的异源组装有助于离子通道在不同组织,不同细胞类型以及不同生理状态下功能多样性的广泛扩展。近年来对于温度敏感TRP通道的异源组装研究也有大量报道,但杂合通道的功能方面我们却知之甚少。
在本课题主要研究了杂合TRPV1/TRPV3通道在热、化合物及电位激活过程中的通道功能特性。同时作者还将通道异源组装的研究扩展到其它温度敏感TRP通道蛋白亚基。结果表明杂合TRPV1/TRPV3通道对TRPV1的激活剂和拮抗剂也都非常敏感;杂合TRPV1/TRPV3通道具有特定的温度敏感性、激活温度阈值和由热引发的通道敏化现象。杂合通道门控特性的改变显然是由TRPV1和TRPV3通道亚基间的相互作用所造成的。温度敏感TRP通道异源组装的实验研究中,作者证明了在细胞中表达TRPV1-TRPV3的串联体能够形成单一的杂合TRPV1/TRPV3通道,通过内面向外(inside-out)的膜片钳记录模式可以从表达串联体的细胞中记录到单通道电流。甚至单通道电导也很一致地处于纯合TRPV1和TRPV3通道的电导之间。这个结果和作者前期发表的有关TRPV1和TRPV3共同表达于细胞中可以组成杂合通道的结果一致。而对其它温度敏感TRP离子通道的异源组装研究显示其蛋白亚基间不能形成杂合通道。
综上所述,本研究证明了杂合TRPV1/TRPV3通道在细胞中的异源组装以及杂合通道在热激活及化学激活过程中功能的扩展,杂合通道的形成和功能特性的扩展也许有助于机体更加精确地对各种感觉和痛觉的敏感性进行细微的调节,从而更好地保护机体躲避有害刺激。
As one of the improtant sensory system, temperature reception involved sensing temperature changes to avoid the risk from environmental harm and to maintain the stability of the body. For a long time the mechanism of temperature reception has remained vague due to the molecular thermosensor had not been identified. Recently a group of cation channels referred to as ThermoTRPs by molecular cloning has been confirmed as the main cellular temperature sensors. The finding of temperature-sensitive TRP ion channels provides an experimental basis on the study of the mechanisms of temperature sensation on molecular level.
Previously we have demonstrated that co-expressing of TRPV1and TRPV3subunits yielded heteromeric channels with intermediate single-channel conductance and gating property. And the assembly between thermo-sensitive TRPV subunits appears to be random.
It is generally hypothesized that heteromeric assembly of TRPV channels underlies the molecular basis of fine-tuning of temperature sensation or chemical activation. However, very little is known about the functional properties of the heteromeric channels.In particular, how heteromeric TRPV1/TRPV3channels respond to heat and other stimuli remains unknown. Given the dramatic functional differences between TRPV1and TRPV3homomeric channels, it is of great interest to understand how heteromeric channels formed between them preserve the physiological properties of each subunit type and respond to benign or noxious stimuli.
In the present study, we investigated the functional properties of heteromeric TRPV1/TRPV3channel activated by voltage, chemicals and heat. We also extended our study to the assembly of other heteromeric Thermo-sensitive TRP channels.
Our results demonstrate that heteromeric TRPV1/TRPV3channels exhibit distinct temperature sensitivity, activation threshold, and heat-induced sensitization. Changes in gating properties apparently originate from interactions between TRPV1and TRPV3subunits. Thus, our results suggest that heteromeric TRPV1/TRPV3channels may serve as polymodal receptor for detecting tempertature changes and chemical irritants, especially noxicious stimuli.They may provide targets of novel therapeutic potentials for fine-tuning heat sensitivity as well as neuronal pain.
引文
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