MAPK signaling and a mobile scaffold complex regulate AMPA receptor transport to modulate synaptic strength

Hoerndli, Frédéric; Brockie, Penelope J.; Wang, Rui; Mellem, Jerry E.; Kallarackal, Angy J.; Doser, Rachel L; Pierce, Dayton M; Madsen, David M.; Maricq, Andres V.

doi:10.1016/j.celrep.2022.110577

Cited by 11 publications

(7 citation statements)

References 88 publications

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“…The 14-3-3 family of homo and heterodimeric adaptor proteins associate with a variety of other proteins, including several kinases and phosphatases (Thompson and Goldspink, 2021;Obsilova and Obsil, 2020) (Box 2). Genetic studies further showed that CaMKII-dependent phosphorylation at the N-terminal part of KLC-2 (S240 and S276) and MAPKsignaling could positively regulate an AMPA-receptor subunit (GLR-1) transport in C. elegans (Hoerndli et al, 2015;Hoerndli et al, 2022). Together, these findings suggested that site-specific phosphorylation by a distinct set of kinases could activate Kinesin-1 in specific contexts and promote intracellular transport (Figures 1A,B).…”

Section: Effects Of Kinesin-1 Phosphorylation On Cargo-motor Interactionmentioning

confidence: 87%

Phosphoregulation of Kinesins Involved in Long-Range Intracellular Transport

Kumari

Ray

2022

Front. Cell Dev. Biol.

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Kinesins, the microtubule-dependent mechanochemical enzymes, power a variety of intracellular movements. Regulation of Kinesin activity and Kinesin-Cargo interactions determine the direction, timing and flux of various intracellular transports. This review examines how phosphorylation of Kinesin subunits and adaptors influence the traffic driven by Kinesin-1, -2, and -3 family motors. Each family of Kinesins are phosphorylated by a partially overlapping set of serine/threonine kinases, and each event produces a unique outcome. For example, phosphorylation of the motor domain inhibits motility, and that of the stalk and tail domains induces cargo loading and unloading effects according to the residue and context. Also, the association of accessory subunits with cargo and adaptor proteins with the motor, respectively, is disrupted by phosphorylation. In some instances, phosphorylation by the same kinase on different Kinesins elicited opposite outcomes. We discuss how this diverse range of effects could manage the logistics of Kinesin-dependent, long-range intracellular transport.

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Section: Effects Of Kinesin-1 Phosphorylation On Cargo-motor Interactionmentioning

confidence: 87%

Phosphoregulation of Kinesins Involved in Long-Range Intracellular Transport

Kumari

Ray

2022

Front. Cell Dev. Biol.

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“…So, to better understand our results above ( Figure 2C and E ), we analyzed GLR-1 transport in mcu-1(lf ) and with Ru360 treatment. To do this, we visualized individual GLR-1::GFP transport by photobleaching a section (~40 µm) of the AVA neurites ( Figure 2—video 1 ) as previously described ( Hoerndli et al, 2022 ; Doser et al, 2020 ). Interestingly, we found that both mcu-1(lf ) and Ru360 treatment decreased the amount of GLR-1 transport by ~50% ( Figure 2F and G ).…”

Section: Resultsmentioning

confidence: 99%

“…Although presynaptic changes contribute to synaptic transmission strength, the number of ionotropic glutamate receptors, especially the α-amino-3-hydroxy-5-methyl-4-isoxazole (AMPA) subtype (AMPARs), at the postsynaptic membrane is a strong correlate of synaptic strength. Changes in synaptic expression of AMPARs is a calcium (Ca 2+ )-dependent, multi-step process involving long-distance transport of the receptors by molecular motors ( Kim and Lisman, 2001 ; Setou et al, 2002 ; Hoerndli et al, 2013 ; Esteves da Silva et al, 2015 ; Hangen et al, 2018 ; Hoerndli et al, 2022 ), delivery of AMPAR-containing vesicles to synaptic sites ( Yang et al, 2008 ; Hoerndli et al, 2015 ), exocytosis and endocytosis of AMPARs to the membrane ( Ehlers, 2000 ; Yudowski et al, 2007 ), as well as reorganization of postsynaptic proteins and cytoskeletal architecture ( Choquet and Triller, 2013 ; Nakahata and Yasuda, 2018 ; Gutiérrez et al, 2021 ).…”

Section: Introductionmentioning

confidence: 99%

Activity-dependent mitochondrial ROS signaling regulates recruitment of glutamate receptors to synapses

Doser,

Knight,

Deihl

et al. 2024

eLife

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Our understanding of mitochondrial signaling in the nervous system has been limited by the technical challenge of analyzing mitochondrial function in vivo. In the transparent genetic model Caenorhabditis elegans, we were able to manipulate and measure mitochondrial ROS (reactive oxygen species) signaling of individual mitochondria as well as neuronal activity of single neurons in vivo. Using this approach, we provide evidence supporting a novel role for mitochondrial ROS signaling in dendrites of excitatory glutamatergic C. elegans interneurons. Specifically, we show that following neuronal activity, dendritic mitochondria take up calcium (Ca2+) via the mitochondrial Ca2+ uniporter MCU-1 that results in an upregulation of mitochondrial ROS production. We also observed that mitochondria are positioned in close proximity to synaptic clusters of GLR-1, the C. elegans ortholog of the AMPA subtype of glutamate receptors that mediate neuronal excitation. We show that synaptic recruitment of GLR-1 is upregulated when MCU-1 function is pharmacologically or genetically impaired but is downregulated by mitoROS signaling. Thus, signaling from postsynaptic mitochondria may regulate excitatory synapse function to maintain neuronal homeostasis by preventing excitotoxicity and energy depletion.

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“…Another piece of evidence for the putative capacity of E2F4 to regulate synaptic function comes from the study by [ 35 ], which showed that E2F4 can regulate genes involved in the MAPK signaling pathway. Although this pathway has been associated with cancer [ 35 ], it is also relevant for synaptic plasticity and AD [ 118 , 119 , 120 ]. A relevant member of the MAPK family of protein kinases is p38 MAPK , the kinase that phosphorylates E2F4 in the Thr conserved motif controlling neuronal tetraploidization [ 13 ].…”

Section: E2f4 As a Multifactorial Regulatormentioning

confidence: 99%

E2F4DN Transgenic Mice: A Tool for the Evaluation of E2F4 as a Therapeutic Target in Neuropathology and Brain Aging

Ramón-Landreau

Sánchez‐Puelles

López-Sánchez

et al. 2022

IJMS

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E2F4 was initially described as a transcription factor with a key function in the regulation of cell quiescence. Nevertheless, a number of recent studies have established that E2F4 can also play a relevant role in cell and tissue homeostasis, as well as tissue regeneration. For these non-canonical functions, E2F4 can also act in the cytoplasm, where it is able to interact with many homeostatic and synaptic regulators. Since E2F4 is expressed in the nervous system, it may fulfill a crucial role in brain function and homeostasis, being a promising multifactorial target for neurodegenerative diseases and brain aging. The regulation of E2F4 is complex, as it can be chemically modified through acetylation, from which we present evidence in the brain, as well as methylation, and phosphorylation. The phosphorylation of E2F4 within a conserved threonine motif induces cell cycle re-entry in neurons, while a dominant negative form of E2F4 (E2F4DN), in which the conserved threonines have been substituted by alanines, has been shown to act as a multifactorial therapeutic agent for Alzheimer’s disease (AD). We generated transgenic mice neuronally expressing E2F4DN. We have recently shown using this mouse strain that expression of E2F4DN in 5xFAD mice, a known murine model of AD, improved cognitive function, reduced neuronal tetraploidization, and induced a transcriptional program consistent with modulation of amyloid-β (Aβ) peptide proteostasis and brain homeostasis recovery. 5xFAD/E2F4DN mice also showed reduced microgliosis and astrogliosis in both the cerebral cortex and hippocampus at 3-6 months of age. Here, we analyzed the immune response in 1 year-old 5xFAD/E2F4DN mice, concluding that reduced microgliosis and astrogliosis is maintained at this late stage. In addition, the expression of E2F4DN also reduced age-associated microgliosis in wild-type mice, thus stressing its role as a brain homeostatic agent. We conclude that E2F4DN transgenic mice represent a promising tool for the evaluation of E2F4 as a therapeutic target in neuropathology and brain aging.

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MAPK signaling and a mobile scaffold complex regulate AMPA receptor transport to modulate synaptic strength

Cited by 11 publications

References 88 publications

Phosphoregulation of Kinesins Involved in Long-Range Intracellular Transport

Phosphoregulation of Kinesins Involved in Long-Range Intracellular Transport

Activity-dependent mitochondrial ROS signaling regulates recruitment of glutamate receptors to synapses

E2F4DN Transgenic Mice: A Tool for the Evaluation of E2F4 as a Therapeutic Target in Neuropathology and Brain Aging

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