Actions of Steroids: New Neurotransmitters

Abstract

Over the past two decades, the classical understanding of steroid action has been updated to include rapid, membrane-initiated, neurotransmitter-like functions. While steroids were known to function on very short time spans to induce physiological and behavioral changes, the mechanisms by which these changes occur are now becoming more clear. In avian systems, rapid estradiol effects can be mediated via local alterations in aromatase activity, which precisely regulates the temporal and spatial availability of estrogens. Acute regulation of brain-derived estrogens has been shown to rapidly affect sensorimotor function and sexual motivation in birds. In rodents, estrogens and progesterone are critical for reproduction, including preovulatory events and female sexual receptivity. Membrane progesterone receptor as well as classical progesterone receptor trafficked to the membrane mediate reproductive-related hypothalamic physiology, via second messenger systems with dopamine-induced cell signals. In addition to these relatively rapid actions, estrogen membrane-initiated signaling elicits changes in morphology. In the arcuate nucleus of the hypothalamus, these changes are needed for lordosis behavior. Recent evidence also demonstrates that membrane glucocorticoid receptor is present in numerous cell types and species, including mammals. Further, membrane glucocorticoid receptor influences glucocorticoid receptor translocation to the nucleus effecting transcriptional activity. The studies presented here underscore the evidence that steroids behave like neurotransmitters to regulate CNS functions. In the future, we hope to fully characterize steroid receptor-specific functions in the brain. IntroductionAt one time, the actions of steroid hormones were thought to mediate physiological changes through changes in gene transcription over an extended time course. This incomplete picture of steroid action has been filled in by the additional understanding that these compounds can have rapid, extragenomic, membrane-initiated actions. It has been known for decades that steroid hormones can have acute actions (within minutes) on physiology (Szego and Davis, 1967), the activity of neurons (Kelly et al., 1976), and the expression of behavior (Hayden-Hixson and Ferris, 1991). More recently, data demonstrate that steroids can and do function in ways that are "neurotransmitter-like," as they are synthesized at precise spatial locations within neural circuits and can act within minutes as local neuromodulators to rapidly regulate cognitive functions and behaviors (Balthazart and Ball,

Estradiol Membrane-Initiated Signaling in the Brain Mediates Reproduction

“…Estradiol signaling rapidly induces neurotransmitter release [45, 86–88] and regulates neurotransmission [89]. Indeed, estradiol (and steroid hormones in general) signaling through membrane receptors resembles GPCR neurotransmitter signaling [90]. Such analyses revealed that the initial action of estradiol, in terms of lordosis, is to engage an inhibitory circuit that involved MPN-projecting β-end neurons [84, 86].…”

Cellular and Molecular Mechanisms of the Effects of Sex Hormones on the Nervous System

“…Recent research demonstrated that steroids can function in a "neurotransmitter-like" way, being synthesized at precise spatial locations within neural circuits in the brain and acting within minutes as local neuromodulators that rapidly regulate cognitive functions and behavior [24][25][26][27].…”

“…The modern understanding of a cell response to a steroid action is that it occurs within the same time frame as that of the G protein-coupled receptors influencing a variety of cellular functions such as gating membrane channels, increasing the intracellular calcium release, activating tyrosine-protein kinase (Src), MAPK, and others [27]. Many studies support a model of integrated signaling that couples signal transduction cascades to transcription in the nucleus, providing an integrated view of hormone signaling in the brain [32].…”

Non-reproductive system effects of progesterone and its non-selective antagonists mifepristone

“…Большое количество современных работ посвящено изучению влияния прогестерона на нервную ткань и функцию центральной нервной системы (ЦНС) [25,27,33]. Доказана способность прогестерона связываться с рецепторами к нему в ЦНС и модулировать поведение и настроение млекопитающих через геномный и неге-номный пути влияния [50]. Также прогестерон может синтезироваться в самой нервной системе, поэтому он еще классифицируется как нейростероид.…”