NCAM promotes assembly and activity-dependent remodeling of the postsynaptic signaling complex

Sytnyk, Vladimir; Leshchyns’ka, Iryna; Nikonenko, Alexander G.; Schachner, Melitta

doi:10.1083/jcb.200604145

Cited by 111 publications

(92 citation statements)

References 49 publications

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“…The neural cell adhesion molecule NCAM and, in particular, its largest NCAM180 isoform, is one of such components (14,25). Delivery of adhesion molecules to nascent synapses during development or to activated synapses during induction of long term potentiation was described as quantal, i.e.…”

Section: Discussionmentioning

confidence: 99%

“…To analyze this possibility, we developed a mathematical model to predict the behavior of NCAM180GFP in the membrane. NCAM180 has been shown to bind via the intracellular domain to spectrin molecules (25,35) and is expected to interact via the extracellular domain with extracellular domains of other adhesion molecules in the synaptic cleft (Fig. 3A).…”

Section: Ncam180gfp Fluorescence Recovers Nonuniformly In the Postsynmentioning

confidence: 99%

“…To identify postsynaptic regions in NCAM180GFP transfected neurons, synaptic boutons of hippocampal neurons maintained in culture for 2 weeks were loaded with the lipophilic dye FM4-64 by a brief incubation in high K ϩ solution (47 mM K ϩ , 90 s) in the presence of the dye (12,25,33,34). NCAM180GFP accumulations in dendrites apposed to FM4-64 clusters were then identified as postsynaptic ( Fig.…”

Section: Ncam180gfp Fluorescence Recovers Nonuniformly In the Postsynmentioning

confidence: 99%

“…Membrane-In mature neurons, NCAM180 accumulates postsynaptically (25,26). To identify postsynaptic regions in NCAM180GFP transfected neurons, synaptic boutons of hippocampal neurons maintained in culture for 2 weeks were loaded with the lipophilic dye FM4-64 by a brief incubation in high K ϩ solution (47 mM K ϩ , 90 s) in the presence of the dye (12,25,33,34).…”

Section: Ncam180gfp Fluorescence Recovers Nonuniformly In the Postsynmentioning

confidence: 99%

“…In humans, genetic variations in the NCAM gene have been reported to confer risk factors associated with bipolar affective disorders and schizophrenia (22)(23)(24). The largest isoform of NCAM, NCAM180, accumulates in the postsynaptic membrane and recruits the spectrin scaffold, NMDA-type glutamate receptors, and Ca 2ϩ /calmodulin-dependent protein kinase ␣ (CaMKII␣) (25)(26)(27), whereas polysialic acid attached to NCAM restrains the signaling through GluN2B-containing NMDA receptors, a process that is required for synaptic plasticity and learning (28).…”

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confidence: 99%

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Immobilized Pool of NCAM180 in the Postsynaptic Membrane Is Homeostatically Replenished by the Flux of NCAM180 from Extrasynaptic Regions

Leshchyns’ka

Tanaka

Schachner

et al. 2011

Journal of Biological Chemistry

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Homeostatic mechanisms maintaining high levels of adhesion molecules in synapses over prolonged periods of time remain incompletely understood. We used fluorescence recovery after photobleaching experiments to analyze the steady state turnover of the immobile pool of green fluorescent protein-labeled NCAM180, the largest postsynaptically accumulating isoform of the neural cell adhesion molecule (NCAM). We show that there is a continuous flux of NCAM180 to the postsynaptic membrane from nonsynaptic regions of dendrites by diffusion. In the postsynaptic membrane, the newly delivered NCAM180 slowly intermixes with the immobilized pool of NCAM180. Preferential immobilization and accumulation of NCAM180 in the postsynaptic membrane is reduced after disruption of the association of NCAM180 with the spectrin cytoskeleton and in the absence of the homophilic interactions of NCAM180 in synapses. Our observations indicate that the homophilic interactions and binding to the cytoskeleton promote immobilization of NCAM180 and its accumulation in the postsynaptic membrane. Flux of NCAM180 from extrasynaptic regions and its slow intermixture with the immobile pool of NCAM180 in the postsynaptic membrane may be important for the continuous homeostatic replenishment of NCAM180 protein at synaptic contacts without compromising the long term synaptic contact stability.Neurons are assembled into circuits via specialized contacts, called synapses, that are essential for information processing, learning, and storage in the brain. Synapses are stable long lasting structures (1-3). This stability is at least partially rendered by a number of cell adhesion molecules accumulating in the pre-and postsynaptic membranes (4 -9). During development, cell adhesion molecules are delivered to nascent synapses in intracellular organelles or as cell surface aggregates (10 -12). A similar type of quantal delivery of adhesion molecules has been also observed during induction of long term potentiation (13). Long lasting stability of synapses (months or years), however, suggests that synaptic pools of cell adhesion molecules (protein life time hours or days) have to be also homeostatically and continuously replenished over prolonged periods of time without compromising synapse stability and composition. Mechanisms of such replenishment remain poorly understood.Among synaptic adhesion molecules, the neural cell adhesion molecule (NCAM), 2 a member of the immunoglobulin superfamily of adhesion molecules, was shown to be involved in mechanical stabilization of interneuronal contacts and their transformation into synapses (12,14). In mice, deficiency in NCAM results in impaired long term potentiation, increased aggression and anxiety, deficits in spatial learning, and exploratory behavior (15-21). In humans, genetic variations in the NCAM gene have been reported to confer risk factors associated with bipolar affective disorders and schizophrenia (22)(23)(24). The largest isoform of NCAM, NCAM180, accumulates in the postsynaptic membrane and recruits the s...

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Section: Discussionmentioning

confidence: 99%

Section: Ncam180gfp Fluorescence Recovers Nonuniformly In the Postsynmentioning

confidence: 99%

Section: Ncam180gfp Fluorescence Recovers Nonuniformly In the Postsynmentioning

confidence: 99%

Section: Ncam180gfp Fluorescence Recovers Nonuniformly In the Postsynmentioning

confidence: 99%

mentioning

confidence: 99%

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Immobilized Pool of NCAM180 in the Postsynaptic Membrane Is Homeostatically Replenished by the Flux of NCAM180 from Extrasynaptic Regions

Leshchyns’ka

Tanaka

Schachner

et al. 2011

Journal of Biological Chemistry

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Neuromechanobiology: An Expanding Field Driven by the Force of Greater Focus

Motz

Kabat

Saxena

et al. 2021

Adv Healthcare Materials

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The brain processes information by transmitting signals through highly connected and dynamic networks of neurons. Neurons use specific cellular structures, including axons, dendrites and synapses, and specific molecules, including cell adhesion molecules, ion channels and chemical receptors to form, maintain and communicate among cells in the networks. These cellular and molecular processes take place in environments rich of mechanical cues, thus offering ample opportunities for mechanical regulation of neural development and function. Recent studies have suggested the importance of mechanical cues and their potential regulatory roles in the development and maintenance of these neuronal structures. Also suggested are the importance of mechanical cues and their potential regulatory roles in the interaction and function of molecules mediating the interneuronal communications. In this review, the current understanding is integrated and promising future directions of neuromechanobiology are suggested at the cellular and molecular levels. Several neuronal processes where mechanics likely plays a role are examined and how forces affect ligand binding, conformational change, and signal induction of molecules key to these neuronal processes are indicated, especially at the synapse. The disease relevance of neuromechanobiology as well as therapies and engineering solutions to neurological disorders stemmed from this emergent field of study are also discussed.

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Cargo hold and delivery: Ankyrins, spectrins, and their functional patterning of neurons

Lorenzo

2020

Cytoskeleton

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The highly polarized, typically very long, and nonmitotic nature of neurons present them with unique challenges in the maintenance of their homeostasis. This architectural complexity serves a rich and tightly controlled set of functions that enables their fast communication with neighboring cells and endows them with exquisite plasticity. The submembrane neuronal cytoskeleton occupies a pivotal position in orchestrating the structural patterning that determines local and long‐range subcellular specialization, membrane dynamics, and a wide range of signaling events. At its center is the partnership between ankyrins and spectrins, which self‐assemble with both remarkable long‐range regularity and micro‐ and nanoscale specificity to precisely position and stabilize cell adhesion molecules, membrane transporters, ion channels, and other cytoskeletal proteins. To accomplish these generally conserved, but often functionally divergent and spatially diverse, roles these partners use a combinatorial program of a couple of dozens interacting family members, whose code is not fully unraveled. In a departure from their scaffolding roles, ankyrins and spectrins also enable the delivery of material to the plasma membrane by facilitating intracellular transport. Thus, it is unsurprising that deficits in ankyrins and spectrins underlie several neurodevelopmental, neurodegenerative, and psychiatric disorders. Here, I summarize key aspects of the biology of spectrins and ankyrins in the mammalian neuron and provide a snapshot of the latest advances in decoding their roles in the nervous system.

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NCAM promotes assembly and activity-dependent remodeling of the postsynaptic signaling complex

Cited by 111 publications

References 49 publications

Immobilized Pool of NCAM180 in the Postsynaptic Membrane Is Homeostatically Replenished by the Flux of NCAM180 from Extrasynaptic Regions

Immobilized Pool of NCAM180 in the Postsynaptic Membrane Is Homeostatically Replenished by the Flux of NCAM180 from Extrasynaptic Regions

Neuromechanobiology: An Expanding Field Driven by the Force of Greater Focus

Cargo hold and delivery: Ankyrins, spectrins, and their functional patterning of neurons

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