Vanden Abeele Fabien, Zholos Alexander, Bidaux Gabriel, Shuba Yaroslav, Thebault Stephanie, Beck Benjamin, Flourakis Matthieu, Panchin Yuri, Skryma Roman, Prevarskaya Natalia
INSERM U800, Equipe Labellisée par la Ligue contre le Cancer, Villeneuve d'Ascq F-59650, France and Universite Lille 1, Villeneuve d'Ascq F-59650, France.
J Biol Chem. 2006 Dec 29;281(52):40174-82. doi: 10.1074/jbc.M605779200. Epub 2006 Nov 2.
TRPM8 represents an ion channel activated by cold temperatures and cooling agents, such as menthol, that underlies the cold-induced excitation of sensory neurons. Interestingly, the only human tissue outside the peripheral nervous system, in which the expression of TRPM8 transcripts has been detected at high levels, is the prostate, a tissue not exposed to any essential temperature variations. Here we show that the TRPM8 cloned from human prostate and heterologously expressed in HEK-293 cells is regulated by the Ca(2+)-independent phospholipase A(2) (iPLA(2)) signaling pathway with its end products, lysophospholipids (LPLs), acting as its endogenous ligands. LPLs induce prominent prolongation of TRPM8 channel openings that are hardly detectable with other stimuli (e.g. cold, menthol, and depolarization) and that account for more than 90% of the total channel open time. Down-regulation of iPLA(2) resulted in a strong inhibition of TRPM8-mediated functional responses and abolished channel activation. The action of LPLs on TRPM8 channels involved either changes in the local lipid bilayer tension or interaction with the critical determinant(s) in the transmembrane channel core. Based on this, we propose a novel concept of TRPM8 regulation with the involvement of iPLA(2) stimulation. This mechanism employs chemical rather than physical (temperature change) signaling and thus may be the main regulator of TRPM8 activation in organs not exposed to any essential temperature variations, as in the prostate gland.
瞬时受体电位香草酸亚型8（TRPM8）是一种由低温和冷却剂（如薄荷醇）激活的离子通道，是感觉神经元冷诱导兴奋的基础。有趣的是，在外周神经系统之外，唯一检测到TRPM8转录本高水平表达的人体组织是前列腺，该组织未经历任何显著的温度变化。在这里，我们表明，从人前列腺克隆并在人胚肾293（HEK-293）细胞中异源表达的TRPM8受不依赖钙离子的磷脂酶A2（iPLA2）信号通路调控，其终产物溶血磷脂（LPLs）作为其内源性配体。LPLs可显著延长TRPM8通道的开放时间，而其他刺激（如寒冷、薄荷醇和去极化）几乎检测不到这种延长，且LPLs引起的通道开放时间占总通道开放时间的90%以上。iPLA2的下调导致TRPM8介导的功能反应受到强烈抑制，并消除通道激活。LPLs对TRPM8通道的作用涉及局部脂质双层张力的变化或与跨膜通道核心关键决定因素的相互作用。基于此，我们提出了一种涉及iPLA2刺激的TRPM8调节新概念。这种机制采用化学而非物理（温度变化）信号传导，因此可能是未经历任何显著温度变化的器官（如前列腺）中TRPM8激活的主要调节因子。
