Schlichter Rémy, Keller Anne Florence, De Roo Mathias, Breton Jean-Didier, Inquimbert Perrine, Poisbeau Pierrick
Institut des Neurosciences Cellulaires et Intégratives-Centre National de la Recherche Scientifique (CNRS), Université Louis Pasteur, 67084 Strasbourg Cedex, France.
J Mol Neurosci. 2006;28(1):33-51. doi: 10.1385/jmn:28:1:33.
Steroids exert long-term modulatory effects on numerous physiological functions by acting at intracellular/nuclear receptors influencing gene transcription. Steroids and neurosteroids can also rapidly modulate membrane excitability and synaptic transmission by interacting with ion channels, that is, ionotropic neurotransmitter receptors or voltage-dependent Ca2+ or K+ channels. More recently, the cloning of a plasma membrane-located G protein-coupled receptor for progestins in various species has suggested that steroids/neurosteroids could also influence second-messenger pathways by directly interacting with specific membrane receptors. Here we review the experimental evidence implicating steroids/neurosteroids in the modulation of synaptic transmission and the evidence for a role of endogenously produced neurosteroids in such modulatory effects. We present some of our recent results concerning inhibitory synaptic transmission in lamina II of the spinal cord and show that endogenous 5alpha-reduced neurosteroids are produced locally in lamina II and modulate synaptic gamma-aminobutyric acid A(GABAA) receptor function during development, as well as during inflammatory pain. The production of 5alpha-reduced neurosteroids is controlled by the endogenous activation of the peripheral benzodiazepine receptor (PBR), which initiates the first step of neurosteroidogenesis by stimulating the translocation of cholesterol across the inner mitochondrial membrane. Tonic neurosteroidogenesis observed in immature animals was decreased during postnatal development, resulting in an acceleration of GABAA receptor-mediated miniature inhibitory postsynaptic current (mIPSC) kinetics observed in the adult. Stimulation of the PBR resulted in a prolongation of GABAergic mIPSCs at all ages and was observed during inflammatory pain. Neurosteroidogenesis might play an important role in the control of nociception at least at the spinal cord level.
类固醇通过作用于影响基因转录的细胞内/核受体，对多种生理功能发挥长期调节作用。类固醇和神经类固醇还可通过与离子通道相互作用，即离子型神经递质受体或电压依赖性Ca2+或K+通道，快速调节膜兴奋性和突触传递。最近，在各种物种中克隆出一种位于质膜的孕激素G蛋白偶联受体，这表明类固醇/神经类固醇也可能通过直接与特定膜受体相互作用来影响第二信使途径。在此，我们综述了涉及类固醇/神经类固醇调节突触传递的实验证据，以及内源性产生的神经类固醇在这种调节作用中发挥作用的证据。我们展示了一些关于脊髓II层抑制性突触传递的最新研究结果，表明内源性5α-还原神经类固醇在II层局部产生，并在发育过程以及炎症性疼痛期间调节突触γ-氨基丁酸A（GABAA）受体功能。5α-还原神经类固醇的产生受外周苯二氮䓬受体（PBR）的内源性激活控制，PBR通过刺激胆固醇跨线粒体内膜的转运启动神经类固醇生成的第一步。在未成熟动物中观察到的持续性神经类固醇生成在出生后发育过程中减少，导致成年动物中GABAA受体介导的微小抑制性突触后电流（mIPSC）动力学加速。刺激PBR在所有年龄段均导致GABA能mIPSCs延长，且在炎症性疼痛期间也可观察到。神经类固醇生成可能至少在脊髓水平的伤害性感受控制中发挥重要作用。
