Physiological consequences of membrane-initiated estrogen signaling in the brain

Abstract

Many of the actions of 17beta-estradiol (E2) in the central nervous system (CNS) are mediated via the classical nuclear steroid receptors, ERalpha and ERbeta, which interact with the estrogen response element to modulate gene expression. In addition to the nuclear-initiated estrogen signaling, E2 signaling in the brain can occur rapidly within minutes prior to any sufficient effects on transcription of relevant genes. These rapid, membrane-initiated E2 signaling mechanisms have now been characterized in many brain regions, most importantly in neurons of the hypothalamus and hippocampus. Furthermore, our understanding of the physiological effects of membrane-initiated pathways is now a major field of interest in the hypothalamic control of reproduction, energy balance, thermoregulation and other homeostatic functions as well as the effects of E2 on physiological and pathophysiological functions of the hippocampus. Membrane signaling pathways impact neuronal excitability, signal transduction, cell death, neurotransmitter release and gene expression. This review will summarize recent findings on membrane-initiated E2 signaling in the hypothalamus and hippocampus and its contribution to the control of physiological and behavioral functions.

Rapid steroid hormone actions via membrane receptors

“…E 2 has multiple effects throughout the central nervous system, many of which have been attributed to membrane rapid signaling, most importantly in neurons of the hypothalamus and hippocampus. The membrane-initiated estrogen signaling involves the rapid activation of the same common membrane delineated pathways including PKC, PI3K-Akt, and ERK-MAPK described in other systems [97]. These signaling cascades were found to change membrane excitability within a matter of seconds while simultaneously eliciting new gene transcription.…”

Sex differences in the physiology of eating

“…The classical mode of action of nuclear ER involves binding to estrogen-response elements (ERE), which, in turn, bind to DNA and affect gene transcription, usually over the course of hours to days (125,326). More recently, it has been found that ER␣ and ER␤, as well as a variety of novel ER, are expressed outside the nucleus, usually on cell membranes (428,475,548,602,759). In addition to genomic effects via non-ERE transcription promotors, membrane ER have rapid (i.e., within seconds) nongenomic effects.…”

“…The effects of ovariectomy and estradiol treatment, however, did not differ between wild-type mice and a different strain of GPR30 Ϫ/Ϫ mice (795). A second novel ER, Gq-mER, is expressed on the cell membranes of proopiomelanocortin (POMC), dopamine, and GABA neurons in the arcuate nucleus of the hypothalamus (576,601,602). Gq-mER reduces the activation of potassium channels on GABA B and -opioid receptors and affects the expression of NPY and other neuropeptides involved in the control of energy homeostasis.…”

Post-synaptic Density-95 (PSD-95) Binding Capacity of G-protein-coupled Receptor 30 (GPR30), an Estrogen Receptor That Can Be Identified in Hippocampal Dendritic Spines

“…Such non-genomic E2 effects can also have significant cellular and physiologic consequences as well, as membrane-initiated E2 stimuli can impact neuronal excitability, neurotransmitter release, and neuronal survival (59).…”