The sigma1 protein as a target for the non-genomic effects of neuro(active)steroids: molecular, physiological, and behavioral aspects.
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.
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.
François P
FP
Monnet
Tangui
T
Maurice
D000818:Animals; D001519:Behavior / Q000187:drug effects / Q000502:physiology*; D001522:Behavior, Animal / Q000187:drug effects / Q000502:physiology; D002490:Central Nervous System / Q000187:drug effects / Q000378:metabolism*; D004347:Drug Interactions; D006801:Humans; D007858:Learning / Q000187:drug effects / Q000502:physiology; D008024:Ligands; D008568:Memory / Q000187:drug effects / Q000502:physiology; D018377:Neurotransmitter Agents / Q000494:pharmacology; D011963:Receptors, GABA-A / Q000187:drug effects / Q000378:metabolism; D016194:Receptors, N-Methyl-D-Aspartate / Q000187:drug effects / Q000378:metabolism; D017480:Receptors, sigma / Q000819:agonists / Q000235:genetics / Q000502:physiology*; D013256:Steroids / Q000502:physiology*
D008024:Ligands; D018377:Neurotransmitter Agents; D011963:Receptors, GABA-A; D016194:Receptors, N-Methyl-D-Aspartate; D017480:Receptors, sigma; D013256:Steroids