Signaling from synapse to nucleus: the logic behind the mechanisms

Deisseroth, Karl; Mermelstein, P.; Xia, Houhui; Tsien, Richard W.

doi:10.1016/s0959-4388(03)00076-x

Cited by 330 publications

(267 citation statements)

References 82 publications

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“…Such signals that are initiated by E2 at the plasma membrane can trigger intracellular signaling events that result in gene transcription. New gene transcription can result from E2 activation of multiple intracellular kinase cascades including MAPK, phosphoinositide 3-kinase (PI3K), cAMP-protein kinase (PKA) and protein kinase C (PKC) pathways (Watters et al, 1997, Bi et al, 2001, Cato et al, 2002, Yang et al, 2003, Deisseroth et al, 2003. These events are often termed rapid signaling cascades because they are initiated at the plasma membrane or in the cytoplasm and occur much faster than ERE-driven events (Bryant et al, 2005, Björnström andSjöberg, 2005).…”

Section: Membrane-initiated Signaling Of E2mentioning

confidence: 99%

Membrane-initiated estrogen signaling in hypothalamic neurons

Kelly

Rønnekleiv

2008

Molecular and Cellular Endocrinology

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SummaryIt is well known that many of the actions of 17β-estradiol (E2) in the central nervous system are mediated via intracellular receptor/transcription factors that interact with steroid response elements on target genes. However, there is compelling evidence for membrane steroid receptors for estrogen in hypothalamic and other brain neurons. But it is not well understood how estrogen signals via membrane receptors, and how these signals impact not only membrane excitability but also gene transcription in neurons. Indeed, it has been known for sometime that E2 can rapidly alter neuronal activity within seconds, indicating that some cellular effects can occur via membrane delimited events. In addition, E2 can affect second messenger systems including calcium mobilization and a plethora of kinases to alter cell signaling. Therefore, this review will consider our current knowledge of rapid membrane-initiated and intracellular signaling by E2 in the hypothalamus, the nature of receptors involved and how they contribute to homeostatic functions. KeywordsERα; ERβ; GPCR (G protein-coupled receptor); mER (membrane estrogen receptor that is a GPCR) Electrophysiological studies in the 1960's and 1970's suggested that gonadal steroids could directly modulate the electrical activity of hypothalamic neurons

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Section: Membrane-initiated Signaling Of E2mentioning

confidence: 99%

Membrane-initiated estrogen signaling in hypothalamic neurons

Kelly

Rønnekleiv

2008

Molecular and Cellular Endocrinology

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“…Presynaptic Ca V s regulate neurotransmitter release (3), and postsynaptic Ca V s activate the transcriptional regulators cAMP-response element-binding protein (CREB) and nuclear factor of activated T-cells (NFAT) (4,5) and thus modulate long term potentiation (6). These functions reflect both the diversity of Ca V isoforms expressed in brain (7)(8)(9)(10)(11) and their differential subcellular localization in neurons (12)(13)(14)(15).…”

mentioning

confidence: 99%

Reciprocal Interactions Regulate Targeting of Calcium Channel β Subunits and Membrane Expression of α1 Subunits in Cultured Hippocampal Neurons

Obermair

Schlick

Biase

et al. 2010

Journal of Biological Chemistry

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Auxiliary ␤ subunits modulate current properties and mediate the functional membrane expression of voltage-gated Ca 2؉ channels in heterologous cells. In brain, all four ␤ isoforms are widely expressed, yet little is known about their specific roles in neuronal functions. Here, we investigated the expression and targeting properties of ␤ subunits and their role in membrane expression of Ca V 1.2 ␣ 1 subunits in cultured hippocampal neurons. Quantitative reverse transcription-PCR showed equal expression, and immunofluorescence showed a similar distribution of all endogenous ␤ subunits throughout dendrites and axons. High resolution microscopy of hippocampal neurons transfected with six different V5 epitope-tagged ␤ subunits demonstrated that all ␤ subunits were able to accumulate in synaptic terminals and to colocalize with postsynaptic Ca V 1.2, thus indicating a great promiscuity in ␣ 1 -␤ interactions. In contrast, restricted axonal targeting of ␤ 1 and weak colocalization of ␤ 4b with Ca V 1.2 indicated isoform-specific differences in local channel complex formation. Membrane expression of external hemagglutinin epitope-tagged Ca V 1.2 was strongly enhanced by all ␤ subunits in an isoform-specific manner. Conversely, mutating the ␣-interaction domain of Ca V 1.2 (W440A) abolished membrane expression and targeting into dendritic spines. This demonstrates that in neurons the interaction of a ␤ subunit with the ␣-interaction domain is absolutely essential for membrane expression of ␣ 1 subunits, as well as for the subcellular localization of ␤ subunits, which by themselves possess little or no targeting properties.Voltage-gated Ca 2ϩ channels (Ca V ) 3 provide key pathways for Ca 2ϩ entry into neurons and translate membrane depolarization into neurotransmitter secretion and gene regulation.Ca V s are composed of a pore-forming ␣ 1 subunit and the auxiliary ␣ 2 ␦ and ␤ subunits (1). Whereas the ␣ 1 subunits are responsible for voltage sensing and ion conduction, the auxiliary subunits have been implicated in membrane targeting and modulation of channel properties (for review see Ref.2). Presynaptic Ca V s regulate neurotransmitter release (3), and postsynaptic Ca V s activate the transcriptional regulators cAMP-response element-binding protein (CREB) and nuclear factor of activated T-cells (NFAT) (4, 5) and thus modulate long term potentiation (6). These functions reflect both the diversity of Ca V isoforms expressed in brain (7-11) and their differential subcellular localization in neurons (12-15).Four distinct ␤ isoforms have been identified (16 -19), all of which are expressed in brain (20 -23). They contain an Src homology 3 domain and a guanylate kinase domain (24 -27). However, the guanylate kinase fold is modified so that it can bind with high affinity to the so-called ␣-interaction domain (AID) in the intracellular I-II linker of Ca V ␣ 1 subunits (28, 29). The Src homology 3 and the guanylate kinase-like domains are highly conserved among the four genes encoding ␤ subunits (Cacnb1-b4; Fig. 1C), whereas t...

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“…However, relatively little is known about how signals are transported from synapse to nucleus to regulate transcription. Many types of synaptic stimulation induce depolarization and electrochemical signaling to rapidly alter transcription in the nucleus (5). A slower, more persistent mechanism of signaling to the nucleus involves the transport of soluble molecules from stimulated synapses to the nucleus (6,7).…”

mentioning

confidence: 99%

Importin-mediated retrograde transport of CREB2 from distal processes to the nucleus in neurons

Lai¹,

Zhao²,

Ch’ng³

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

104

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Signals received at distal synapses of neurons must be conveyed to the nucleus to initiate the changes in transcription that underlie long-lasting synaptic plasticity. The presence of importin nuclear transporters and of select transcription factors at synapses raises the possibility that importins directly transport transcription factors from synapse to nucleus to modulate gene expression. Here, we show that cyclic AMP response element binding protein 2 (CREB2)/activating transcription factor 4 (ATF4), a transcriptional repressor that modulates long-term synaptic plasticity and memory, localizes to distal dendrites of rodent hippocampal neurons and neurites of Aplysia sensory neurons (SNs) and binds to specific importin ␣ isoforms. Binding of CREB2 to importin ␣ is required for its transport from distal dendrites to the soma and for its translocation into the nucleus. CREB2 accumulates in the nucleus during long-term depression (LTD) but not long-term potentiation of rodent hippocampal synapses, and during LTD but not long-term facilitation (LTF) of Aplysia sensory-motor synapses. Time-lapse microscopy of CREB2 tagged with a photoconvertible fluorescent protein further reveals retrograde transport of CREB2 from distal neurites to the nucleus of Aplysia SN during phenylalaninemethionine-arginine-phenylalanine-amide (FMRFamide)-induced LTD. Together, our findings indicate that CREB2 is a novel cargo of importin ␣ that translocates from distal synaptic sites to the nucleus after stimuli that induce LTD of neuronal synapses.Aplysia ͉ hippocampus ͉ transcription ͉ long-term depression ͉ dendra S ynaptic plasticity is critical to cognition and memory formation. Long-lasting forms of synaptic plasticity require both transcription and translation (1-3), and specific patterns and strengths of synaptic stimulation trigger changes in neuronal gene expression (4). However, relatively little is known about how signals are transported from synapse to nucleus to regulate transcription. Many types of synaptic stimulation induce depolarization and electrochemical signaling to rapidly alter transcription in the nucleus (5). A slower, more persistent mechanism of signaling to the nucleus involves the transport of soluble molecules from stimulated synapses to the nucleus (6, 7). Recent studies have indicated that this type of transport may involve the active nuclear import pathway (8-10).In the classical nuclear import pathway, proteins bearing nuclear localization signals (NLSs) bind an adaptor protein of the importin ␣ family, which in turn binds the importin ␤1 nuclear transporter. Importin ␤1 mediates facilitated translocation of this heterotrimeric complex across the nuclear pore. In neurons, importins may also function to carry signals from distal neuronal processes to the soma and into the nucleus (8-11). This finding raises a critical question: what are the synaptically localized cargoes of importins that translocate to the nucleus to alter transcription during synaptic plasticity?One attractive class of potential importin...

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Signaling from synapse to nucleus: the logic behind the mechanisms

Cited by 330 publications

References 82 publications

Membrane-initiated estrogen signaling in hypothalamic neurons

Membrane-initiated estrogen signaling in hypothalamic neurons

Reciprocal Interactions Regulate Targeting of Calcium Channel β Subunits and Membrane Expression of α1 Subunits in Cultured Hippocampal Neurons

Importin-mediated retrograde transport of CREB2 from distal processes to the nucleus in neurons

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