Monnet François P, Maurice Tangui
Unité 705 de l'Institut National de la Santé et de la Recherche Médicale, Unité Mixte de Recherche 7157 du Centre National de la Recherche Scientifique, Université de Paris V et VII, Hôpital Lariboisière-Fernand Widal, Paris, France.
J Pharmacol Sci. 2006 Feb;100(2):93-118. doi: 10.1254/jphs.cr0050032. Epub 2006 Feb 11.
Steroids synthesized in the periphery or de novo in the brain, so called 'neurosteroids', exert both genomic and nongenomic actions on neurotransmission systems. Through rapid modulatory effects on neurotransmitter receptors, they influence inhibitory and excitatory neurotransmission. In particular, progesterone derivatives like 3alpha-hydroxy-5alpha-pregnan-20-one (allopregnanolone) are positive allosteric modulators of the gamma-aminobutyric acid type A (GABA(A)) receptor and therefore act as inhibitory steroids, while pregnenolone sulphate (PREGS) and dehydroepiandrosterone sulphate (DHEAS) are negative modulators of the GABA(A) receptor and positive modulators of the N-methyl-D-aspartate (NMDA) receptor, therefore acting as excitatory neurosteroids. Some steroids also interact with atypical proteins, the sigma (sigma) receptors. Recent studies particularly demonstrated that the sigma1 receptor contributes effectively to their pharmacological actions. The present article will review the data demonstrating that the sigma1 receptor binds neurosteroids in physiological conditions. The physiological relevance of this interaction will be analyzed and the impact on physiopathological outcomes in memory and drug addiction will be illustrated. We will particularly highlight, first, the importance of the sigma1-receptor activation by PREGS and DHEAS which may contribute to their modulatory effect on calcium homeostasis and, second, the importance of the steroid tonus in the pharmacological development of selective sigma1 drugs.
在外周合成或在脑内从头合成的类固醇，即所谓的“神经甾体”，对神经传递系统具有基因组和非基因组作用。通过对神经递质受体的快速调节作用，它们影响抑制性和兴奋性神经传递。特别是，像3α-羟基-5α-孕烷-20-酮（别孕烷醇酮）这样的孕酮衍生物是γ-氨基丁酸A型（GABAA）受体的正性变构调节剂，因此作为抑制性类固醇起作用，而孕烯醇酮硫酸盐（PREGS）和脱氢表雄酮硫酸盐（DHEAS）是GABAA受体的负性调节剂和N-甲基-D-天冬氨酸（NMDA）受体的正性调节剂，因此作为兴奋性神经甾体起作用。一些类固醇还与非典型蛋白，即σ受体相互作用。最近的研究特别表明，σ1受体对它们的药理作用有重要贡献。本文将综述证明σ1受体在生理条件下与神经甾体结合的数据。将分析这种相互作用的生理相关性，并说明其对记忆和药物成瘾中生理病理结果的影响。我们将特别强调，首先，PREGS和DHEAS激活σ1受体的重要性，这可能有助于它们对钙稳态的调节作用；其次，类固醇张力在选择性σ1药物药理开发中的重要性。
