Calcium Channels Link the Muscle-Derived Synapse Organizer Laminin β2 to Bassoon and CAST/Erc2 to Organize Presynaptic Active Zones

Chen, Jie; Billings, Sara E.; Nishimune, Hiroshi

doi:10.1523/jneurosci.3771-10.2011

Cited by 88 publications

(150 citation statements)

References 82 publications

(130 reference statements)

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“…More recent studies confirmed the early observations which demonstrated laminin-β2 being directly involved in maintaining normal presynaptic differentiation during NMJ development (Noakes et al, 1995a;Nishimune et al, 2004;Chen et al, 2011;Chand et al, 2015).…”

Section: Laminin-β2supporting

confidence: 72%

“…This is further supported with the colocalisation of Bassoon with P/Q-type VGCCs, in which both displayed similar pattern of distribution at the NMJ Nishimune et al, 2016). The direct interaction between active zone components and VGCCs help anchors active zones to the presynaptic membrane (Chen et al, 2011;Chand et al, 2015). The interaction between the active zone components and the VGCCs is also physiologically important as demonstrated in the study by Kiyonaka et al (2007), in which the interaction between the C-terminus of RIM1 and β4 subunit of VGCCs suppresses the inhibition of VGCC activation thus allowing further influx of calcium ions.…”

Section: Active Zonessupporting

confidence: 54%

“…To further support this, Chen et al (2011) demonstrated interaction between VGCCs and active zone components through immunoprecipitation study, in which β1b and β4 subunits of VGCCs were able to interact directly with the active zone component, Bassoon. Thus, explaining the reduction in the expression of Bassoon staining at P/Q-and N-type knockout NMJs, by 35% and 32% respectively (Chen et al, 2011). More importantly, decreased expression of laminin-β2 at the synaptic cleft of double knockout (N-and P/Q-type VGCCs)…”

Section: Laminin-β2mentioning

confidence: 92%

“…was observed, suggesting the required presence of VGCCs to bind to laminin-β2 in the synaptic cleft (Chen et al, 2011). Therefore, the interaction between VGCCs and laminin-β2 is likely required to anchor the active zone components at the presynaptic membrane thus contributing to assembly and stability of active zone.…”

Section: Laminin-β2mentioning

confidence: 98%

“…Active zone components also interact with voltage-gated calcium channels (VGCCs) as shown through the binding of Bassoon to β1b and β4 subunit of the presynaptic VGCCs, with CAST also having direct interaction with β1b subunit (Chen et al, 2011) (See section 1.1.1;…”

Section: Active Zonesmentioning

confidence: 99%

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The role of synaptic laminins-α4 and -β2 in maturation and maintenance of the neuromuscular synapse

Lee¹

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The proper development, maturation and maintenance of the neuromuscular junction (NMJ) are critical for ensuring efficient neurotransmission. Proteins found within the basal lamina of the synaptic cleft, namely the laminins family, are heavily involved in maintaining normal structure and function of the NMJ. In particular, individual laminin chains such as laminin-β2, -α4 and -α5 play essential roles in organisation and maintenance of the NMJ. These laminin chains interact together to form three synapse specific laminin heterotrimers; laminin-221 (α2β2γ1), laminin-421 (α4β2γ1) and laminin-521 (α5β2γ1).Laminin-β2 is the common laminin chain found in each of these synapse specific laminin heterotrimers. In-vitro it has been shown to play a key role in the organisation of the presynaptic elements at the NMJ via its interaction and clustering of the N-and P/Q-type voltage-gated calciums (VGCCs). During development of the NMJ, both N-and P/Q-type VGCCs are involved in mediating neurotransmitter release. As the NMJ matures, P/Q-type becomes the dominant channel involved in release while N-type takes on the role of fine-tuning calcium influx. Laminin-α4, on the other hand, ensures proper alignment of presynaptic active zones to postjunctional folds at the NMJ, with its loss resulting in misalignment of these specialisations. Furthermore, this laminin chain has been shown to be involved in the maintenance of the NMJ with the observation of premature ageing features at 6 months of age (6MO) in laminin-α4 deficient mice (lama4 NMJs.In conclusion, this thesis has identified the significant roles laminins-α4 and -β2 play at the NMJ during development, maturation and maintenance. Results suggest that laminin-β2 is not only an important regulator of the presynaptic maturation through the switching of VGCCs and clustering of P/Q-type VGCCs, but also equally important for maturation of the postsynaptic apparatus. Ipropose that laminin-β2 is important for the maturation of each component at the NMJ. The altered responses in transmission properties presented by aged wild-type NMJs which resembled adult lama4 -/-, preceded by altered expression of laminin-α4 chain, strongly suggest that laminin-α4 is not only important for maintaining proper alignment of pre-to postsynaptic NMJ, but also essentially important for maintaining a healthy adult NMJ. Finally, I observed early alterations in expression of laminin-α4 at the NMJs in diseased mouse model of ALS prior to any appearance of neuromotor impairment, suggesting a potential involvement of laminins in NMJ degeneration associated with neuromuscular disorders such as ALS.ii

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Section: Laminin-β2supporting

confidence: 72%

Section: Active Zonessupporting

confidence: 54%

Section: Laminin-β2mentioning

confidence: 92%

Section: Laminin-β2mentioning

confidence: 98%

Section: Active Zonesmentioning

confidence: 99%

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The role of synaptic laminins-α4 and -β2 in maturation and maintenance of the neuromuscular synapse

Lee¹

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Collagen XIII and Other ECM Components in the Assembly and Disease of the Neuromuscular Junction

Heikkinen

Härönen

Norman

et al. 2019

The Anatomical Record

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Alongside playing structural roles, the extracellular matrix (ECM) acts as an interaction platform for cellular homeostasis, organ development, and maintenance. The necessity of the ECM is highlighted by the diverse, sometimes very serious diseases that stem from defects in its components. The neuromuscular junction (NMJ) is a large peripheral motor synapse differing from its central counterparts through the ECM included at the synaptic cleft. Such synaptic basal lamina (BL) is specialized to support NMJ establishment, differentiation, maturation, stabilization, and function and diverges in molecular composition from the extrasynaptic ECM. Mutations, toxins, and autoantibodies may compromise NMJ integrity and function, thereby leading to congenital myasthenic syndromes (CMSs), poisoning, and autoimmune diseases, respectively, and all these conditions may involve synaptic ECM molecules. With neurotransmission degraded or blocked, muscle function is impaired or even prevented. At worst, this can be fatal. The article reviews the synaptic BL composition required for assembly and function of the NMJ molecular machinery through the lens of studies primarily with mouse models but also with human patients. In‐depth focus is given to collagen XIII, a postsynaptic‐membrane‐spanning but also shed ECM protein that in recent years has been revealed to be a significant component for the NMJ. Its deficiency in humans causes CMS, and autoantibodies against it have been recognized in autoimmune myasthenia gravis. Mouse models have exposed numerous details that appear to recapitulate human NMJ phenotypes relatively faithfully and thereby can be readily used to generate information necessary for understanding and ultimately treating human diseases. Anat Rec, 2019. © 2019 Wiley Periodicals, Inc.

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Active zone density is conserved during synaptic growth but impaired in aged mice

Chen

Maekawa

Nishimune

2011

J of Comparative Neurology

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Presynaptic active zones are essential structures for synaptic vesicle release, but the developmental regulation of their number and maintenance during aging at mammalian neuromuscular junctions (NMJs) remains unknown. Here, we analyzed the distribution of active zones in developing, mature, and aged mouse NMJs by immunohistochemical detection of the active zone-specific protein Bassoon. Bassoon is a cytosolic scaffolding protein essential for the active zone assembly in ribbon synapses and some brain synapses. Bassoon staining showed a punctate pattern in nerve terminals and axons at the nascent NMJ on embryonic days 16.5–18.5. Three-dimensional reconstruction of NMJs revealed that the majority of Bassoon puncta within an NMJ were attached to the presynaptic membrane from postnatal day 0 to adulthood, and colocalized with another active zone protein Piccolo. During postnatal development, the number of Bassoon puncta increased as the size of the synapses increased. Importantly, the density of Bassoon puncta remained relatively constant from postnatal day 0 to 54 at 2.3 puncta/μm2, while the synapse size increased 3.3-fold. However, Bassoon puncta density and signal intensity were significantly attenuated at the NMJs of 27-month-old aged mice. These results suggest that synapses maintain the density of synaptic vesicle release sites while the synapse size changes, but this density becomes impaired during aging.

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Calcium Channels Link the Muscle-Derived Synapse Organizer Laminin β2 to Bassoon and CAST/Erc2 to Organize Presynaptic Active Zones

Cited by 88 publications

References 82 publications

The role of synaptic laminins-α4 and -β2 in maturation and maintenance of the neuromuscular synapse

The role of synaptic laminins-α4 and -β2 in maturation and maintenance of the neuromuscular synapse

Collagen XIII and Other ECM Components in the Assembly and Disease of the Neuromuscular Junction

Active zone density is conserved during synaptic growth but impaired in aged mice

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