Departamento de Farmacobiología, Centro de Investigación y de Estudios Avanzados del Instituto Politécnico Nacional, Calzada de los Tenorios No. 235, México City 14330, México.
Hippocampus. 2018 Aug;28(8):557-567. doi: 10.1002/hipo.22958. Epub 2018 May 21.
In addition to its prominent role as an energetic substrate in the brain, lactate is emerging as a signaling molecule capable of controlling neuronal excitability. The finding that the lactate-activated receptor (hydroxycarboxylic acid receptor 1; HCA1) is widely expressed in the brain opened up the possibility that lactate exerts modulation of neuronal activity via a transmembranal receptor-linked mechanism. Here, we show that lactate causes biphasic modulation of the intrinsic excitability of CA1 pyramidal cells. In the low millimolar range, lactate or the HCA1 agonist 3,5-DHBA reduced the input resistance and membrane time constant. In addition, activation of HCA1 significantly blocked the fast inactivating sodium current and increased the delay from inactivation to a conducting state of the sodium channel. As the observed actions occurred in the presence of 4-CIN, a blocker of the neuronal monocarboxylate transporter, the possibility that lactate acted via neuronal metabolism is unlikely. Consistently, modulation of the intrinsic excitability was abolished when CA1 pyramidal cells were dialyzed with pertussis toxin, indicating the dependency of a G -protein-coupled receptor. The activation of HCA1 appears to serve as a restraining mechanism during enhanced network activity and may function as a negative feedback for the astrocytic production of lactate.
除了在大脑中作为一种活跃的能量底物发挥突出作用外，乳酸也正在成为一种能够控制神经元兴奋性的信号分子。发现乳酸激活受体（羟基羧酸受体 1；HCA1）在大脑中广泛表达，这使得乳酸通过跨膜受体相关机制对神经元活动进行调节成为可能。在这里，我们表明乳酸引起 CA1 锥体神经元内在兴奋性的双相调节。在低毫摩尔范围内，乳酸或 HCA1 激动剂 3,5-DHBA 降低了输入电阻和膜时间常数。此外，HCA1 的激活显著阻断了快速失活的钠电流，并增加了钠通道从失活到导电状态的延迟。由于观察到的作用发生在神经元单羧酸转运蛋白的阻断剂 4-CIN 的存在下，因此乳酸不太可能通过神经元代谢起作用。一致地，当 CA1 锥体细胞用百日咳毒素透析时，内在兴奋性的调制被消除，表明 G 蛋白偶联受体的依赖性。HCA1 的激活似乎在增强的网络活动期间充当一种抑制机制，并且可以作为星形胶质细胞产生乳酸的负反馈。
