The role of laminins in the organization and function of neuromuscular junctions

Abstract

The synapse between motor neurons and skeletal muscle is known as the neuromuscular junction (NMJ). Proper alignment of presynaptic and post-synaptic structures of motor neurons and muscle fibers, respectively, is essential for efficient motor control of skeletal muscles. The synaptic cleft between these two cells is filled with basal lamina. Laminins are heterotrimer extracellular matrix molecules that are key members of the basal lamina. Laminin α4, α5, and β2 chains specifically localize to NMJs, and these laminin isoforms play a critical role in maintenance of NMJs and organization of synaptic vesicle release sites known as active zones. These individual laminin chains exert their role in organizing NMJs by binding to their receptors including integrins, dystroglycan, and voltage-gated calcium channels (VGCCs). Disruption of these laminins or the laminin-receptor interaction occurs in neuromuscular diseases including Pierson syndrome and Lambert-Eaton myasthenic syndrome (LEMS). Interventions to maintain proper level of laminins and their receptor interactions may be insightful in treating neuromuscular diseases and aging related degeneration of NMJs.

Early endplate remodeling and skeletal muscle signaling events following rat hindlimb suspension

“…Increased activity, such as different modes of exercise training, typically results in expansion of the neuromuscular junction size. Reduced patterns of neuromuscular activity due to denervation, injury, bed rest, and other form of disuse including microgravity at spaceflight, various muscle diseases and aging, also triggers endplate remodeling (for review, see Gonzalez‐Freire, de Cabo, Studenski, & Ferrucci, ; Nishimune, Stanford, & Mori, ; Rogers & Nishimune, ; Rudolf, Khan, Labeit, & Deschenes, ; Tintignac, Brenner, & Rüegg, ; Wilson & Deschenes, ). The molecular mechanisms underlying the effects of neuromuscular activity on endplate structure, function, and plasticity is complex and remains to be fully elucidated.…”

Mapping the molecular and structural specialization of the skin basement membrane for inter-tissue interactions

“…An analogous BM structure can be observed in the neuromuscular junction, where the reticular lamina is excluded and the BM extends protrusions from synaptic active zones toward junctional folds that invaginate the postsynaptic muscle membrane 36 . Laminin–integrin interactions can be observed on both nerve and muscle sides of the BM and play critical roles in the formation and function of neuromuscular junctions 52, 53 . Moreover, COL7 is absent from lung alveoli, blood vessels and kidneys, where different tissues are tightly integrated via the BM that places laminins at both its sides 1, 2, 54, 55, 56 .…”

LAMA2 Neuropathies: Human Findings and Pathomechanisms From Mouse Models

“…Therein, other laminin isoforms are also present, including laminin-421 and -521 (Patton et al, 1997). These three laminin isoforms are essential in establishing and maintaining the structure of NMJs and the alignment of the presynaptic zone (Rogers and Nishimune, 2017). Thus, potentially, loss of laminin chain α2 might affect NMJ formation and function, contributing to the motor phenotype of LAMA2/Lama2.…”

“…However, they normally assemble the presynaptic active zone and properly appose to the acetylcholine receptors (Gilbert et al, 1973). More severe effects on NMJs at pre and post-synaptic zone are instead a consequence of the deletion of laminin chain α4 and/or α5, and particularly in mice devoid of β2 chain (reviewed in Rogers and Nishimune, 2017).…”