Palmitoylation of Estrogen Receptors Is Essential for Neuronal Membrane Signaling

Meitzen, John; Luoma, Jessie I.; Boulware, Marissa I.; Hedges, Valerie L.; Peterson, Brittni M.; Tuomela, Krista; Britson, Kyla A.; Mermelstein, P.

doi:10.1210/en.2013-1172

Cited by 81 publications

(66 citation statements)

References 78 publications

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“…Palmitoylation refers to the addition of the fatty acid, palmitic acid, to specific residues of proteins, typically membrane-associated proteins (Basu 2004). If palmitoylation is inhibited in hippocampal cell cultures, rapid estrogen-induced phosphorylation of cyclic AMP response element binding protein (CREB) is eliminated (Meitzen et al 2013). Furthermore, palmitoylation occurs at specific cysteine sites of ERα and ERβ receptors; when these palmitoylation sites are mutated, rapid estrogen-induced CREB phosphorylation and activation of MAPK and PI3 kinase are blocked (Meitzen et al 2013, Pedram et al 2002).…”

Section: Membrane Associated Estrogen Receptorsmentioning

confidence: 99%

Estrogen receptors in the central nervous system and their implication for dopamine-dependent cognition in females

Almey

Milner

Brake

2015

Hormones and Behavior

235

174

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Over the past 30 years, research has demonstrated that estrogens are not only important for female reproduction, but play a role in a diverse array of cognitive functions. Originally, estrogens were thought to have only one receptor, localized exclusively to the cytoplasm and nucleus of cells. However, it is now known that there are at least three estrogen receptors (ERs): ERα, ERβ and G-protein coupled ER1 (GPER1). In addition to being localized to nuclei, ERα and ERβ are localized to the cell membrane, and GPER1 is also observed at the cell membrane. The mechanism through which ERs are associated with the membrane remains unclear, but palmitoylation of receptors and associations between ERs and caveolin are implicated in membrane association. ERα and ERβ are mostly observed in the nucleus using light microscopy unless they are particularly abundant. However, electron microscopy has revealed that ERs are also found at the membrane in complimentary distributions in multiple brain regions, many of which are innervated by dopamine inputs and were previously thought to contain few ERs. In particular, membrane-associated ERs are observed in the prefrontal cortex, dorsal striatum, nucleus accumbens, and hippocampus, all of which are involved in learning and memory. These findings provide a mechanism for the rapid effects of estrogens in these regions. The effects of estrogens on dopamine-dependent cognition likely result from binding at both nuclear and membrane-associated ERs, so elucidating the localization of membrane-associated ERs helps provide a more complete understanding of the cognitive effects of these hormones.

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Section: Membrane Associated Estrogen Receptorsmentioning

confidence: 99%

Estrogen receptors in the central nervous system and their implication for dopamine-dependent cognition in females

Almey

Milner

Brake

2015

Hormones and Behavior

235

174

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“…Interestingly, E 2 does not interact with mGluRs to increase ERK-dependent CREB phosphorylation in hippocampal cultures from neonatal male rats (Boulware et al 2005), suggesting potentially important sex differences in estrogenic regulation of rapid cell signaling. In female rat hippocampal cultures, the ability of the ERs to associate with mGluRs and phosphorylate CREB is dependent on S-palmitoylation (Meitzen et al 2013), a post-translational modification associated with intracellular protein trafficking (Fukata and Fukata 2010). Although the ability of ERs to associate with mGluRs and phosphorylate CREB through an S-palmitoylation process has not yet been tested in males, this finding may help to explain how ERa and ERb can be shuttled to the plasma membrane to trigger rapid cell-signaling processes in females.…”

Section: Estrogen Receptor Localization and Mechanism Of Action Era Amentioning

confidence: 99%

Sex steroid hormones matter for learning and memory: estrogenic regulation of hippocampal function in male and female rodents

et al. 2015

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Ample evidence has demonstrated that sex steroid hormones, such as the potent estrogen 17b-estradiol (E 2 ), affect hippocampal morphology, plasticity, and memory in male and female rodents. Yet relatively few investigators who work with male subjects consider the effects of these hormones on learning and memory. This review describes the effects of E 2 on hippocampal spinogenesis, neurogenesis, physiology, and memory, with particular attention paid to the effects of E 2 in male rodents. The estrogen receptors, cell-signaling pathways, and epigenetic processes necessary for E 2 to enhance memory in female rodents are also discussed in detail. Finally, practical considerations for working with female rodents are described for those investigators thinking of adding females to their experimental designs.Hormones have long been known to play key roles in regulating learning and memory. Many hormones, including epinephrine, glucocorticoids, and insulin influence learning and memory via inverted U-shaped dose-response relationships in which memory is enhanced by moderate, but not low or high, hormone levels (Roozendaal 2000;Korol and Gold 2007;McNay and Recknagel 2011). Research from the past two decades has demonstrated that sex steroid hormones, particularly the potent estrogen 17b-estradiol (E 2 ), also regulate learning and memory in male and female rodents via an inverted U-shaped dose-response function that is influenced by estrogen receptor expression (Packard and Teather 1997a;Packard 1998;Foster 2012). Yet E 2 has not gained widespread acceptance as a hormonal modulator of memory in both females and males, perhaps because the majority of this research has been conducted in female rodents. Moreover, the common view of E 2 as a "female" hormone may contribute to the misperception that E 2 is not relevant for cognitive function in males. However, considerable evidence supports a vital role for E 2 in mediating neural function and behavior in male rodents. Therefore, it is important for investigators working with males to understand the ways in which E 2 and other sex steroid hormones (e.g., androgens, progestins, and other estrogens) may influence their brain regions and behaviors of interest.Another reason for investigators to be cognizant of sex steroid hormone-induced regulation of learning and memory is that males and females may respond differently to various treatments and environmental factors. A classic example is that of acute stress, which enhances classical conditioning and increases apical CA1 dendritic spine density in male rats, but impairs classical conditioning and decreases CA1 spine density in female rats (Wood and Shors 1998;Shors et al. 2001). Therefore, investigators hoping to comply with National Institutes of Health policies that encourage the inclusion of females in biomedical research must be aware that adding females to a study is not as simple as adding another group. In some ways, females are fundamentally different from males, the most obvious of which is the presence of reproductive...

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“…Moreover, both ERα and ERβ interact with metabotropic glutamate receptor 1 (mGluR1) to rapidly activate hippocampal ERK signaling and promote the phosphorylation of cAMP response element binding protein (CREB) (Boulware et al, 2013; Boulware et al, 2005). The ability of each ER to associate with mGluRs and phosphorylate CREB is dependent on S -palmitoylation (Meitzen et al, 2013), a post-translational modification associated with intracellular protein trafficking (Fukata and Fukata, 2010). This finding helps to explain how ERα and ERβ can be shuttled to the plasma membrane to trigger rapid cell-signaling processes.…”

Section: E2 and The Hippocampusmentioning

confidence: 99%

Molecular mechanisms underlying the memory-enhancing effects of estradiol

Frick

2015

Hormones and Behavior

147

132

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Since the publication of the 1998 special issue of Hormones and Behavior on estrogens and cognition, substantial progress has been made towards understanding the molecular mechanisms through which 17β-estradiol (E2) regulates hippocampal plasticity and memory. Recent research has demonstrated that rapid effects of E2 on hippocampal cell signaling, epigenetic processes, and local protein synthesis are necessary for E2 to facilitate the consolidation of object recognition and spatial memories in ovariectomized female rodents. These effects appear to be mediated by non-classical actions of the intracellular estrogen receptors ERα and ERβ, and possibly by membrane-bound ERs such as the G-protein-coupled estrogen receptor (GPER). New findings also suggest a key role of hippocampally-synthesized E2 in regulating hippocampal memory formation. The present review discusses these findings in detail and suggests avenues for future study.

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Palmitoylation of Estrogen Receptors Is Essential for Neuronal Membrane Signaling

Cited by 81 publications

References 78 publications

Estrogen receptors in the central nervous system and their implication for dopamine-dependent cognition in females

Estrogen receptors in the central nervous system and their implication for dopamine-dependent cognition in females

Sex steroid hormones matter for learning and memory: estrogenic regulation of hippocampal function in male and female rodents

Molecular mechanisms underlying the memory-enhancing effects of estradiol

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