Neuro(active)steroids actions at the neuromodulatory sigma1 (σ1) receptor: Biochemical and physiological evidences, consequences in neuroprotection

Steroids from peripheral sources or synthesized in the brain, i.e. neurosteroids, exert rapid modulations of neurotransmitter responses through specific interactions with membrane receptors, mainly the γ-aminobutyric acid type A (GABAA) receptor and N-methyl-d-aspartate (NMDA) type of glutamate receptor. Progesterone and 3α-hydroxy-5α-pregnan-20-one (allopregnanolone) act as inhibitory steroids while pregnenolone sulfate or dehydroepiandrosterone sulfate act as excitatory steroids. Some steroids also interact with an atypical protein, the sigma1 (σ1) receptor. This receptor has been cloned in several species and is centrally expressed in neurons and oligodendrocytes. Activation of the σ1 receptor modulates cellular Ca2+ mobilization, particularly from endoplasmic reticulum pools, and contributes to the formation of lipid droplets, translocating towards the plasma membrane and contributing to the recomposition of lipid microdomains. The present review details the evidences showing that the σ1 receptor is a target for neurosteroids in physiological conditions. Analysis of the σ1 protein sequence confirmed homologies with the ERG2/emopamil binding protein family but also with the steroidogenic enzymes isopentenyl diphosphate isomerase and 17β-estradiol dehydrogenase. Biochemical and physiological arguments for an interaction of neuro(active)steroids with the σ1 receptor are analyzed and the impact on physiopathological outcomes in neuroprotection is illustrated.