Neuroactive steroid mechanisms and GABA type A receptor subunit assembly in hypothalamic and extrahypothalamic...

Gonadal- and neuronal-derived steroids are capable of altering brain functions through two basic mechanisms: slow (genomic) and rapid (novel nongenomic membrane) types of activities. The genomic activities that are circumscribed to the numerous neuronal and glial expressed receptor actions involve transcriptional processes regulated largely by classical steroids. On the other hand, rapid nongenomic activities are linked to the stereoselective interactions of potent neuroactive steroids. It appears that both of these steroid mechanisms can be successfully evoked at the ligand-gated heteroligomeric GABA type A receptor. However, the precise structural prerequisites and type of molecular steroid interactions implicated in this neuronal target have not been fully investigated. This article reviews the most common subunits (alpha, beta, and gamma) of the native GABA type A receptor involved in signaling pathways of slow and rapid steroidal mechanisms. Different beta-containing compositions (alpha1beta1-3gamma2) are necessary for the slow type of mechanism, whereas different alpha-containing constructs (alpha2-6beta 1/2 gamma2/2L) are linked to the rapid type. Because of the major role played by neuroactive steroids in GABA-dependent neuroendocrine and sociosexual events, distinction of the specific subunit combination is essential not only for elucidating neuronal communicative expressions during such events but also for elucidating their potential neuroprotective role in neurodegenerative disorders.