Calcium-engaged Mechanisms of Nongenomic Action of Neurosteroids

Abstract

Background: Neurosteroids form the unique group because of their dual mechanism of action. Classically, they bind to specific intracellular and/or nuclear receptors, and next modify genes transcription. Another mode of action is linked with the rapid effects induced at the plasma membrane level within seconds or milliseconds. The key molecules in neurotransmission are calcium ions, thereby we focus on the recent advances in understanding of complex signaling crosstalk between action of neurosteroids and calcium-engaged events.Methods: Short-time effects of neurosteroids action have been reviewed for GABAA receptor complex, glycine receptor, NMDA receptor, AMPA receptor, G protein-coupled receptors and sigma-1 receptor, as well as for several membrane ion channels and plasma membrane enzymes, based on available published research.Results: The physiological relevance of neurosteroids results from the fact that they can be synthesized and accumulated in the central nervous system, independently from peripheral sources. Fast action of neurosteroids is a prerequisite for genomic effects and these early events can significantly modify intracellular downstream signaling pathways. Since they may exert either positive or negative effects on calcium homeostasis, their role in monitoring of spatio-temporal Ca2+ dynamics, and subsequently, Ca2+-dependent physiological processes or initiation of pathological events, is evident.Conclusion: Neurosteroids and calcium appear to be the integrated elements of signaling systems in neuronal cells under physiological and pathological conditions. A better understanding of cellular and molecular mechanisms of nongenomic, calcium-engaged neurosteroids action could open new ways for therapeutic interventions aimed to restore neuronal function in many neurological and psychiatric diseases.

Evidence for effective structure‐based neuromodulatory effects of new analogues of neurosteroid allopregnanolone

“…It is also well known that, over the GABA A ‐R, AP may regulate neuroendocrine and/or neuroprotective processes via interactions with various other receptors such as the L‐type Ca 2+ channels, the pregnane X receptor, the liver X receptor, the nicotinic and serotonin type 3 receptors and membrane progesterone G‐coupled protein receptors (mPR), including mPRδ, mPRα and mPRβ . Altogether, these data suggest that the ANS‐evoked structure‐based neuroprotective and/or proliferation‐promoting effects identified in the present study may involve selective interactions with various receptors, including ligand‐gated ion channels and/or G‐coupled protein receptors regulating neuroendocrine and/or neurophysiological activities . In support of this idea, previous studies have shown that neuroblastoma SH‐SY5Ycells express various receptors, including sigma and NMDA receptors, which mediate certain effects of neurosteroids …”

“…79,80 Altogether, these data suggest that the ANS-evoked structure-based neuroprotective and/or proliferation-promoting effects identified in the present study may involve selective interactions with various receptors, including ligand-gated ion channels and/or Gcoupled protein receptors regulating neuroendocrine and/or neurophysiological activities. [81][82][83] In support of this idea, previous studies have shown that neuroblastoma SH-SY5Ycells express various receptors, including sigma and NMDA receptors, which mediate certain effects of neurosteroids. [84][85][86][87][88] In conclusion, the present study, which demonstrates the identification of novel and efficient analogues of the key neuromodulator AP, also opens interesting and promising perspectives with respect to using neurosteroids for the development of structure-based selective and effective strategies against various neuroendocrine and/or neurodegenerative disorders.…”

Neurosteroids as Selective Inhibitors of Glycine Receptor Activity: Structure-Activity Relationship Study on Endogenous Androstanes and Androstenes

“…These compounds and their synthetic analogs are mainly known as potent modulators of GABA A Rs (Chen et al, 2019) and N-methyl-D-aspartate receptors (NMDARs) (Burnell et al, 2019), respectively. Neurosteroids and their synthetic analogs (neuroactive steroids, NAS) have been extensively studied during last three decades as they modify neuronal activity and thus brain function via a fast, non-genomic action (Rebas et al, 2017), by acting as allosteric modulators of various ligandgated ion channels, including GABA A R and GlyR. In brief, NS and NAS are effective modulators of GABA A R-induced chloride current (I GABA ) and their modulatory action is dependent on their structure and subtype (for a review, see: Majewska et al, 1988;Wu et al, 1990;Belelli and Lambert, 2005;Korinek et al, 2011;King, 2013;Zorumski et al, 2013).…”

Biosynthesis and signalling functions of central and peripheral nervous system neurosteroids in health and disease

“…Here, we will review the opposing effects of neurosteroids on GABA A and NMDA receptors [97][98][99]. Neurosteroids also act on several other ion channel receptors, including glycine, AMPA and sigma receptors, which have recently been reviewed by Rebas et al [100].…”