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Calcium-Engaged Mechanisms of Nongenomic Action of Neurosteroids

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Calcium-Engaged Mechanisms of Nongenomic Action of Neurosteroids Calcium-engaged Mechanisms of Nongenomic Action of Neurosteroids The Harvard community has made this article openly available. Please share how this access benefits you. Your story matters Citation Rebas, Elzbieta, Tomasz Radzik, Tomasz Boczek, and Ludmila Zylinska. 2017. “Calcium-engaged Mechanisms of Nongenomic Action of Neurosteroids.” Current Neuropharmacology 15 (8): 1174-1191. doi:10.2174/1570159X15666170329091935. http:// dx.doi.org/10.2174/1570159X15666170329091935. Published Version doi:10.2174/1570159X15666170329091935 Citable link http://nrs.harvard.edu/urn-3:HUL.InstRepos:37160234 Terms of Use This article was downloaded from Harvard University’s DASH repository, and is made available under the terms and conditions applicable to Other Posted Material, as set forth at http:// nrs.harvard.edu/urn-3:HUL.InstRepos:dash.current.terms-of- use#LAA 1174 Send Orders for Reprints to [email protected] Current Neuropharmacology, 2017, 15, 1174-1191 REVIEW ARTICLE ISSN: 1570-159X eISSN: 1875-6190 Impact Factor: 3.365 Calcium-engaged Mechanisms of Nongenomic Action of Neurosteroids BENTHAM SCIENCE Elzbieta Rebas1, Tomasz Radzik1, Tomasz Boczek1,2 and Ludmila Zylinska1,* 1Department of Molecular Neurochemistry, Faculty of Health Sciences, Medical University of Lodz, Poland; 2Boston Children’s Hospital and Harvard Medical School, Boston, USA 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 A R T I C L E H I S T O R Y sigma-1 receptor, as well as for several membrane ion channels and plasma membrane enzymes, based on available published research. Received: August 23, 2016 Revised: December 27, 2016 Accepted: March 15, 2017 Results: The physiological relevance of neurosteroids results from the fact that they can be DOI: synthesized and accumulated in the central nervous system, independently from peripheral sources. 10.2174/1570159X15666170329091935 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. Keywords: Calcium, neurosteroids, nongenomic action, central nervous system, neuroprotection, neuropathology. 1. INTRODUCTION Neurosteroids can exist in the free form or may be converted into sulfate derivatives or fatty acid esters. Sulfate derivatives Steroid hormones affecting brain functions are called of two most popular neurosteroids, DHEA and pregnenolone, neuroactive steroids [1]. Generally, they are classified are even more active than their free forms. Some of typical according to the site of their synthesis. All steroid hormones neurosteroids (e.g. DHEAS, PregS, allopregnanolone, synthesized de novo from cholesterol inside the brain cells androstenedione, THDOC) are specific for various brain belong to a big group named neurosteroids. These compounds cells and their concentration in peripheral tissues is very low are generated from identical precursor – pregnenolone – by [4]. On the other hand, the steroids generated in peripheral enzymes present in various brain regions (Fig. 1) [2, 3]. glands can also modulate CNS functions, as they are able to cross blood-brain barrier due to their lipophilic nature. Some *Address correspondence to these authors at the Department of Molecular of them - particularly progesterone or estradiol - are present Neurochemistry, Faculty of Health Sciences, Medical University: 92- in the brain and peripheral tissues, and their level in blood 215Lodz, 6/8 Mazowiecka Street, Poland; Tel: +4842 272 5680; Fax: +4842 can be higher or similar to the level in the brain. 2725679; E-mail: [email protected] 1875-6190/17 $58.00+.00 ©2017 Bentham Science Publishers Current Neuropharmacology Calcium-engaged Mechanisms of Nongenomic Action of Neurosteroids Current Neuropharmacology, 2017, Vol. 15, No. 8 1175 Fig. (1). Schematic illustration of the main pathways of cholesterol conversion into neurosteroids. DHP-dehydropregnenolone, DHT-dihydrotestosterone Besides classical, genomic action of neurosteroids, their on the crosstalk between nongenomic action of neurosteroids biologically important properties are their fast actions and intracellular calcium events. detected within seconds or minutes. In most cases, neuro- steroids directly affect the membrane specific receptors, but 2. CALCIUM AND NEUROSTEROIDS also interact with the receptors selective for various neurotransmitters and extracellular ligands. Action through 2.1. GABAA Receptors classical intracellular receptors requires a time period Among different γ-aminobutyric acid receptors, the type between minutes and hours and involves transcriptional A (GABAA) is regulated by various neurosteroids. It consists machinery. of several subunits able to bind different agonists such as Most neurosteroids do not exhibit high affinity to benzodiazepines, barbiturates, alcohols, anesthetics and some classical intracellular receptors, thus only a non-classical neuroactive steroids. Most neurosteroids with 3α-hydroxyl action is possible. Nongenomic pathways comprise the group within A-ring (mainly 3α-reduced metabolites of stimulation of numerous membrane receptors, i.e. GABA-, progesterone and deoxycorticosterone, allopregnanolone, glycine-, NMDA- , AMPA/kainate- , sigma- and G-protein 3α,5α-THDOC or androstenediol) are positive allosteric coupled receptors, but also directly activate several type of modulators of GABAAR enhancing GABA-evoked chloride ion channels (VGCC, TRPC) and enzymes. It should be current [8]. This very fast action allows for influx of chloride noted that this fast, non-classical effect appears to be, at least and thus generation of physiological cell response within in part, a prerequisite step for further genomic processes. milliseconds to seconds. Neurosteroids acting as GABAAR The level of neurosteroids fluctuates throughout life, as well agonists show similar properties to GABA including as during pregnancy, stress and aging. Both, genomic and anticonvulsant, sedative-hypnotic, analgesic and anxiolytic nongenomic activity of neurosteroids may contribute to the effects [9]. Based on these observations, several synthetic pathophysiology of various psychiatric disorders, but may neurosteroids (Alfaxalone, Minoxolone, Ganaxolone) are also protect from neurodegenerative insults. Therefore, they frequently used in medicine for premedication and anesthesia. are considered as potentially useful in the treatment of However, it has been established that in some cells, diseases such as depression and anxiety. increased chloride current led to membrane depolarization Calcium ions have been indisputably recognized as a and to activation of L-type of voltage-gated calcium channels crucial element of complex machinery regulating normal [10]. Thereby, GABA may also exhibit non-typical, excitatory neuronal functions. The physiological effects of changes in effect instead of most popular inhibitory action (Fig. 2). Ca2 + concentration can be detected after short time (within Such an atypical GABA role has been mainly observed in seconds), but also after longer time period, when the altered developing cortical neurons or in other immature CNS cells gene expression becomes visible. It is now evident that Ca2+ [11]. In primary cultures of rat cortical neurons, calcium concentration in neurons is tightly controlled by multiple influx induced by GABA was inhibited by PregS, and this 2+ mechanisms [5]. Many of them trigger different Ca - effect was concentration-dependent with an IC50 of 30 µM. dependent signaling pathways which may directly or indirectly The authors suggested that the PregS site of action could be stimulate downstream effectors, thereby controlling and/or different from GABA binding site. Although PregS has inducing changes in neuronal activities. Moreover, the mixed allosteric GABA-agonistic/antagonistic properties, it is disturbances in calcium homeostasis have been documented rather considered as excitatory hormone with anxiogenic and to be associated with neurodegenerative processes and proconvulsant action. The inhibition of GABA-induced several psychiatric diseases [6, 7]. In this review, we focus calcium influx by PregS seems to confirm it [12]. Other 1176 Current Neuropharmacology, 2017, Vol. 15, No. 8 Rebas
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