Cloning, Expression, and Localization of MNAR/PELP1 in Rodent Brain: Colocalization in Estrogen Receptor-α- But Not in Gonadotropin-Releasing Hormone-Positive Neurons

Louisiana State University Health Sciences Center New Orleans, New Orleans, Louisiana, United States
Endocrinology (Impact Factor: 4.5). 01/2006; 146(12):5215-27. DOI: 10.1210/en.2005-0276
Source: PubMed

ABSTRACT MNAR/PELP1 is a recently identified scaffold protein in the human that modulates the nongenomic activity of estrogen receptors by facilitating linkage/cross talk with the Src/Erk activation cascade. We report herein the cloning of rat MNAR/PELP1 and provide new information concerning its distribution in the female rat brain and its degree of colocalization with estrogen receptor-alpha (ER-alpha) and GnRH. PCR-based cloning of MNAR/PELP1 from rat hypothalamus yielded a transcript of approximately 3.4 kb, which shows 86% homology to the published human MNAR/PELP1 sequence and retained all the key binding motifs (PXXP, LXXLL, and glutamic acid clusters) in its primary structure that are known to be critical for its interaction with Src and steroid receptors. RT-PCR revealed that the MNAR/PELP1 transcript is expressed in many regions of the brain, and immunohistochemistry studies showed intense MNAR/PELP1 immunoreactivity (MNAR/PELP1-ir) in areas such as the hypothalamus, cerebral cortex, hippocampus, amygdala, and cerebellum. MNAR/PELP1-ir principally localized in the nucleus, but some cytoplasmic and plasma membrane-associated staining was also observed. MNAR/PELP1-ir was also primarily neuronal, although some localization in glia cells was observed in select brain regions. Colocalization studies revealed that a majority of ER-alpha-positive cells in the brain colocalized MNAR/PELP1-ir. In contrast, MNAR/PELP1-ir rarely colocalized in GnRH neurons. In conclusion, the current study provides evidence that MNAR/PELP1 is expressed in key neural tissues of the rat brain that are known targets of steroid action, that its expression is primarily neuronal, and that MNAR/PELP1-ir is strongly colocalized in ER-alpha, but not GnRH neurons in the rodent brain.

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Available from: Mohammad M Khan, Aug 06, 2014
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    • "The proline-, glutamic acid-, and leucine-rich protein (PELP)1, or modulator of non-genomic actions of estrogen receptor (MNAR), was first identified as a novel binding partner of ERa, with high expression in human brain, testes and mammary glands (Khan et al., 2005; Vadlamudi et al., 2001). PELP1/MNAR contains a conserved LXXLL motif that has been shown to interact with the AF-2 domain of steroid receptors and an SRC homology 3 domain (SH3 domain), which serves as a binding site for SH3 domain proteins (Khan et al., 2005; Vadlamudi et al., 2001). While PELP1/MNAR has been shown to be required for rapid, non-genomic signaling in breast cancer cells (Greger et al., 2007), the role of this protein in regulating either ERa or ERb signaling in neurons has yet to be established. "
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    ABSTRACT: There is now a growing appreciation that estrogen is capable of rapidly activating a number of signaling cascades within the central nervous system. In addition, there are an increasing number of studies reporting that 17β-estradiol, the major biologically active estrogen, can modulate cognition within a rapid time frame. Here we review recent studies that have begun to uncover the molecular and cellular framework which contributes to estrogens ability to rapidly modulate cognition. We first describe the mechanisms by which estrogen receptors (ERs) can couple to intracellular signaling cascades, either directly, or via the transactivation of other receptors. Subsequently, we review the evidence that estrogen can rapidly modulate both neuronal function and structure in the hippocampus and the cortex. Finally, we will discuss how estrogens may influence cognitive function through the modulation of neuronal structure, and the implications this may have on the treatment of a range of brain disorders.
    Frontiers in Neuroendocrinology 08/2014; 36. DOI:10.1016/j.yfrne.2014.08.001 · 7.04 Impact Factor
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    • " human brain , testes , and mammary glands ( Vadlamudi et al . , 2001 ; Khan et al . , 2005 ; ) . PELP1 / MNAR contains a conserved LXXLL motif that has been shown to interact with the AF - 2 domain of steroid receptors and an SRC homology 3 domain ( SH3 domain ) , which serves as a binding site for SH3 domain proteins ( Vadlamudi et al . , 2001 ; Khan et al . , 2005 ) . Although PELP1 / MNAR has been shown to be required for rapid , nongenomic signaling in breast cancer cells ( Boonyaratanakornkit , 2011 ) , the role of this protein in regulating either ERa or ERb signaling in neurons has yet to be established . Another protein called striatin is a 110 - kDa protein that contains a putative caveoli"
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    ABSTRACT: Converging evidence from cellular, electrophysiological, anatomic, and behavioral studies suggests that the remodeling of synapse structure and function is a critical component of cognition. This modulation of neuroplasticity can be achieved through the actions of numerous extracellular signals. Moreover, it is thought that it is the integration of different extracellular signals regulation of neuroplasticity that greatly influences cognitive function. One group of signals that exerts powerful effects on multiple neurologic processes is estrogens. Classically, estrogens have been described to exert their effects over a period of hours to days. However, there is now increasing evidence that estrogens can rapidly influence multiple behaviors, including those that require forebrain neural circuitry. Moreover, these effects are found in both sexes. Critically, it is now emerging that the modulation of cognition by rapid estrogenic signaling is achieved by activation of specific signaling cascades and regulation of synapse structure and function, cumulating in the rewiring of neural circuits. The importance of understanding the rapid effects of estrogens on forebrain function and circuitry is further emphasized as investigations continue to consider the potential of estrogenic-based therapies for neuropathologies. This review focuses on how estrogens can rapidly influence cognition and the emerging mechanisms that underlie these effects. We discuss the potential sources and the biosynthesis of estrogens within the brain and the consequences of rapid estrogenic-signaling on the remodeling of neural circuits. Furthermore, we argue that estrogens act via distinct signaling pathways to modulate synapse structure and function in a manner that may vary with cell type, developmental stage, and sex. Finally, we present a model in which the coordination of rapid estrogenic-signaling and activity-dependent stimuli can result in long-lasting changes in neural circuits, contributing to cognition, with potential relevance for the development of novel estrogenic-based therapies for neurodevelopmental or neurodegenerative disorders.
    Pharmacological reviews 07/2013; 65(4):1318-1350. DOI:10.1124/pr.111.005272 · 17.10 Impact Factor
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    • "PELP1 is capable of coupling estrogen receptors together with signaling intermediates such as Src kinase and PI3K (Cheskis et al 2008), and in breast cancer cells, PELP1 knockdown demonstrates its essential role for mediating estrogen-stimulated Akt activation (Dimple et al 2008). PELP1 protein expression is identified in CNS structures, including the hippocampus, where it is observed to colocalize with ERα (Khan et al 2005). Ultrastructurally, PELP1-ir is found in dendritic spines (T. "
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    ABSTRACT: From its origins in how the brain controls the endocrine system via the hypothalamus and pituitary gland, neuroendocrinology has evolved into a science that now includes hormone action on many aspects of brain function. These actions involve the whole central nervous system and not just the hypothalamus. Advances in our understanding of cellular and molecular actions of steroid hormones have gone beyond the important cell nuclear actions of steroid hormone receptors to include signaling pathways that intersect with other mediators such as neurotransmitters and neuromodulators. This has, in turn, broadened the search for and identification of steroid receptors to include nonnuclear sites in synapses, dendrites, mitochondria, and glial cells, as well as cell nuclei. The study of estrogen receptors and estrogen actions on processes related to cognition, mood, autonomic regulation, pain, and neuroprotection, among other functions, has led the way in this new view of hormone actions on the brain. In this review, we summarize past and current work in our laboratory on this topic. This exciting and growing field involving many laboratories continues to reshape our ideas and approaches to neuroendocrinology both at the bench and the bedside.
    Behavioral Neuroscience 02/2012; 126(1):4-16. DOI:10.1037/a0026708 · 2.73 Impact Factor
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