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Rapid Central Corticosteroid Effects: Evidence for Membrane Glucocorticoid Receptors in the Brain1
Integrative and Comparative Biology, Sep 2005 by Tasker, Jeffrey G, Di, Shi, Malcher-Lopes, Renato
SYNOPSIS.
Glucocorticoid secretion occurs in a circadian pattern and in response to stress. Among the broad array of glucocorticoid actions are multiple effects in the brain, including negative feedback regulation of hypothalamic hormone secretion. The negative feedback of glucocorticoids occurs on both rapid and delayed time scales, reflecting different regulatory mechanisms. While the slow glucocorticoid effects are widely held to involve regulation of gene transcription, the rapid effects are too fast to invoke genomic mechanisms. We provide a brief overview of multiple lines of evidence for membrane-associated glucocorticoid receptors in the brain, with an emphasis on our recent findings of a rapid, G protein-dependent glucocorticoid action in the rat hypothalamus. We have observed a novel mechanism of rapid glucocorticoid inhibition of parvocellular neuroendocrine cells of the hypothalamic paraventricular nucleus (PVN) mediated by the retrograde release of endocannabinoids and suppression of synaptic glutamate release. This acute glucocorticoid action may underlie the rapid inhibitory effect of glucocorticoids on hypothalamic neuroendocrine function, and provides a potential model for the rapid glucocorticoid effects that occur in several areas of the brain.
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In addition to the classical delayed actions of glucocorticoids that rely on transcriptional regulation, it is becoming increasingly clear that glucocorticoids, like other steroid hormones, also have rapid actions both in peripheral tissues and in the central nervous system. Glucocorticoids have been shown to exert fast effects on the brain to regulate various centrally controlled functions in different species, including stressrelated locomotor activity (Sandi et al., 1996), sexual behavior (Rose et al., 1993), learning and memory (de Quervain et al., 1998), and hypothalamic hormone secretion (Jones et al., 1977; Liu et al., 1995; Papanek et al., 1997). A major role of glucocorticoids is to provide negative feedback regulation of hypothalamic hormone systems, seen especially in the control of the stress hormone, corticotropin releasing hormone (CRH) (see Keller-Wood and Dallman, 1984 for review), but also in that of other hypothalamic hormones, such as vasopressin (Papanek and Raff, 1994) and thyrotropin releasing hormone (TRH) (Brabant et al., 1987). We present here a brief overview of the evidence for rapid corticosteroid signaling through activation of putative membrane glucocorticoid receptors in different parts of the brain and in different vertebrate species, with an emphasis on rapid feedback effects in the hypothalamus. This review is not intended to present an exhaustive survey of the literature, but to provide an overview of recent findings supporting the existence of membrane glucocorticoid receptors in the brain and their link to G protein signaling mechanisms.
THE HYPOTHALAMIC-PITUITARY-ADRENAL AXIS
Glucocorticoids are released from the adrenal cortex in response to activation of the hypothalamic-pituitaryadrenal (HPA) axis. Activation of the HPA axis consists of stimulation of parvocellular neuroendocrine cells in the PVN and the release of the hypophysiotropic hormones CRH and vasopressin into the pituitary portal plexus. These hormones then stimulate the release of adrenocorticotropic hormone (ACTH) from the anterior lobe of the pituitary gland, which accesses the adrenal cortex via the general circulation to cause the secretion of glucocorticoids. Glucocorticoid levels in the blood fluctuate in a diurnal pattern, with relatively high levels found in the circadian morning in humans and low levels at night (rodents and other nocturnal animals show the opposite circadian pattern). Activation of the HPA axis occurs in response to both physiological and psychological stresses. Stress activation of the HPA axis is characterized by circulating levels of glucocorticoids that reach micromolar concentrations.
Glucocorticoids secreted by the adrenal glands in response to stress activation of the HPA axis exert widespread actions that serve to coordinate a variety of responses in the organism appropriate to the demands of a stressful situation. While these actions are probably not fast enough to contribute to the immediate sympathetic fight-or-flight response necessary for survival in the face of an immediate threat, they are fast enough to set the tone for sustaining short-term behavioral adaptations necessary for survival in a dangerous situation. The multiple somatic actions of stress-elevated circulating glucocorticoid levels include, among others, reduced glucose storage and enhanced glucose metabolism, suppression of immune system function, and inhibition of the inflammatory response to injury. Glucocorticoids released during stress also exert profound effects on endocrine function by acting both in the periphery and in the brain. Of particular interest for the purpose of this review are the relatively rapid glucocorticoid effects on hypothalamic neuroendocrine function. Indeed, glucocorticoids have inhibitory effects on different hypothalamic neuroendocrine systems, including but not limited to the negative feedback regulation of the HPA axis by suppression of the secretion of CRH and vasopressin from PVN parvocellular neurons (de Kloet, 2000; Herman et al., 1996). The glucocorticoid negative feedback regulation of the HPA axis occurs both rapidly, by inhibiting CRH release, as well as more slowly, via down-regulation of CRH and vasopressin expression in PVN neurons (Keller-Wood and Dallman, 1984). The canonical transcriptional actions of glucocorticoids are mediated by supposed diffusion of the steroid hormone across the cell membrane and its binding to cytosolic corticosteroid receptors. The interaction of the steroid with its receptor forms a receptor-ligand complex and triggers the translocation of the receptor to the nucleus, where it binds to a hormone response element and regulates gene transcription (Falkenstein et al., 2000). These classical transcriptional effects of glucocorticoids are not the subject of this review, but rather we will address the mechanisms responsible for the rapid effects of glucocorticoids, focusing on recent evidence for putative membrane glucocorticoid receptors. Findings from studies in several different animal models suggest that rapid glucocorticoid actions in the brain are mediated by membrane receptors and non-transcriptional signaling mechanisms.
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