Active Zone Protein Bassoon Co-Localizes with Presynaptic Calcium Channel, Modifies Channel Function, and Recovers from Aging Related Loss by Exercise

Nishimune, Hiroshi; Numata, Tomohiro; Chen, Jie; Aoki, Yudai; Wang, Yonghong; Starr, Miranda P.; Mori, Yasuo; Stanford, John A.

doi:10.1371/journal.pone.0038029

Cited by 55 publications

(95 citation statements)

References 55 publications

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“…We labelled NMJs with antibodies to three AZ markers: bassoon (encoded by Bsn), piccolo (encoded by Pclo) and P/Q VGCC (specifically the subunit encoded by Cacna1a). In WT mice, these proteins presented with a clear punctate staining (Nishimune et al, 2012) (Fig. 2A-C), but the fluorescence intensity of these three markers was drastically reduced in both integrin-α3 +/− and integrin-α3 −/− NMJs ( Fig.…”

Section: Integrin-α3 Is Concentrated At the Azs Of Nmjs And Regulatesmentioning

confidence: 99%

“…In vitro expression studies demonstrate that bassoon positively regulates the activity of the P/Q VGCC, prolonging its opening times (Nishimune et al, 2012); therefore, the reduced localisation of bassoon at integrin-α3 +/− NMJs might cause a decreased influx of Ca 2+ at these terminals, which would be exacerbated when the concentration of external Ca 2+ is reduced. Given the deficiency of bassoon and piccolo at adult integrin-α3 +/− AZs (Fig.…”

Section: Role Of Integrin-α3 At the Azmentioning

confidence: 99%

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Multiple roles of integrin-α3 at the neuromuscular junction

Ross

Webster

Lechertier

et al. 2017

Journal of Cell Science

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The neuromuscular junction (NMJ) is the synapse between motoneurons and skeletal muscle, and is responsible for eliciting muscle contraction. Neurotransmission at synapses depends on the release of synaptic vesicles at sites called active zones (AZs). Various proteins of the extracellular matrix are crucial for NMJ development; however, little is known about the identity and functions of the receptors that mediate their effects. Using genetically modified mice, we find that integrin-α3 (encoded by Itga3), an adhesion receptor at the presynaptic membrane, is involved in the localisation of AZ components and efficient synaptic vesicle release. Integrin-α3 also regulates integrity of the synapse -mutant NMJs present with progressive structural changes and upregulated autophagy, features commonly observed during ageing and in models of neurodegeneration. Unexpectedly, we find instances of nerve terminal detachment from the muscle fibre; to our knowledge, this is the first report of a receptor that is required for the physical anchorage of pre-and postsynaptic elements at the NMJ. These results demonstrate multiple roles of integrin-α3 at the NMJ, and suggest that alterations in its function could underlie defects that occur in neurodegeneration or ageing.

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Section: Integrin-α3 Is Concentrated At the Azs Of Nmjs And Regulatesmentioning

confidence: 99%

Section: Role Of Integrin-α3 At the Azmentioning

confidence: 99%

Multiple roles of integrin-α3 at the neuromuscular junction

Ross

Webster

Lechertier

et al. 2017

Journal of Cell Science

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“…Thus, P/Q-type VGCCs and the direct interaction with laminin-β2 are necessary for efficient organisation of active zone elements. This could be due to the closer localisation of P/Q-type to release sites, being more favourable in interaction with presynaptic components in comparison with N-type VGCCs which are localised further away from the release sites (Urbano et al, 2002;Nudler et al, 2003) despite both VGCCs having direct interaction with presynaptic proteins such as Bassoon, SNAP25 and Syntaxin 1A (Kim & Catterall, 1997;Zhong et al, 1999;Chen et al, 2011;Nishimune et al, 2012).…”

Section: Failure In Switching Of N-to P/q-type Vgcc Clusters At Maturmentioning

confidence: 99%

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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“…Multiple VGCCs sub-types coexist at a single synapse and interact to induce release of transmitter (Regehr & Mintz, 1994;Dunlap et al, 1995). P/Q-type VGCCs are spatially located in closer proximity to release sites compared to the more abundant N-type VGCCs Nudler et al, 2003;Urbano et al, 2003;Nishimune et al, 2012). This close spatial localisation may well be the reason P/Q-type VGCCs play a more prominent role in the mature junction where efficient bulk release of transmitter is required (Rosato-Siri et al,…”

Section: Laminin-β2 Deficient Neuromuscular Junctions Maintained Depementioning

confidence: 99%

“…Prior research has shown that the maintenance of active zone composition, and the molecular organisation of key components is strongly influenced by P/Q-type VGCCs (Nishimune et al, 2004;Nishimune et al, 2012). Previous research suggests that P/Q-type VGCCs interact directly with SNAP25 and syntaxin via the pore forming α-subunits, while Bassoon is capable of interacting with the β1b and β4 subunits of VGCCs (Kim & Catterall, 1997;Zhong et al, 1999;Chen et al, 2011;Nishimune et al, 2012).…”

Section: Structures As the Neuromuscular Junction Maturesmentioning

confidence: 99%

The functional role of laminins-α4 and -β2 in development of the neuromuscular junction

Chand¹

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The precise development and organisation of the neuromuscular junction (NMJ) is critical for the production of efficient neurotransmission signals. Disruption of these specialisations may result in severely altered transmission properties at the NMJ.Signalling and adhesion molecules have long been established to be key mediators in the distribution of synaptic specialisations. The basal lamina acts to maintain stability of the associated tissue and contains a number of these signalling and adhesion molecules. The laminins, a family of large multimeric proteins, are one of the key components of the basal lamina that act as specific cell regulators and provide mechanical stability. Laminins have been shown to form an interconnecting network that assists in stabilisation of the basal lamina and provides attachment sites for other basal lamina components. The synapse specific laminin chains, -α4, -α5, and -β2, play an essential role in differentiation and organisation of the NMJ. These chains form the laminin isoforms, laminin-221 (α2β2γ1), laminin-421 (α4β2γ1), and laminin-521 (α5β2γ1).Laminin-β2, found in each of the three synapse specific isoforms, has been shown to organise presynaptic specialisations at the developing NMJ. In vitro laminin-β2 is able to interact directly with N-type and P/Q-type voltage-gated calcium This study examined the role of laminin-β2 in the organisation of N-and P/Q-type VGCCs at active zones of developing postnatal day 8 (P8) and matured, postnatal day 18 (P18) NMJs.The contribution of each channel to the release of transmitter was assessed using intracellular electrode recordings of end-plate potentials (EPPs). The VGCC toxins, ω-conotoxin-GVIA and ω-agatoxin-IVA, were used to specifically target N-and P/Q-type NMJs displayed significantly higher levels of synaptic depression under high frequency stimuli and altered paired pulse facilitation compared to wild-type littermates. Analysis of the binomial parameters of neurotransmitter release demonstrated a decrease in quantal release as a result of a decrease in the number of active release sites, but not in the average probability of transmitter release from these sites. Our functional findings suggest alterations in the short-term plasticity of the NMJ and possibly defective recycling of ii synaptic vesicles and/or the calcium handling at lama4 -/-NMJs. We propose that alterations to synapsin I and its associated molecules may be partly responsible for the changes in neurotransmission observed at lama4 -/-NMJs. Our findings demonstrate altered distribution and expression of presynaptic components associated with active zones, specifically an increase in the number of synaptic vesicles and a decrease in the density of the fluorescently labelled Bassoon at the active zone region. Our results suggest that the fewer active release sites may compensate for the deficits of the lama4 -/-NMJs by alterations to pre-and postsynaptic specialisations.In conclusion, this thesis has identified that laminins-α4 and -β2 play fundamental role...

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Active Zone Protein Bassoon Co-Localizes with Presynaptic Calcium Channel, Modifies Channel Function, and Recovers from Aging Related Loss by Exercise

Cited by 55 publications

References 55 publications

Multiple roles of integrin-α3 at the neuromuscular junction

Multiple roles of integrin-α3 at the neuromuscular junction

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

The functional role of laminins-α4 and -β2 in development of the neuromuscular junction

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