Muscle-Specific Agrin Isoforms Reduce Phosphorylation of AChR γ and δ Subunits in Cultured Muscle Cells

Meier, Thomas; Rüegg, Markus A.; Wallace, Bruce G.

doi:10.1006/mcne.1998.0685

Cited by 7 publications

(1 citation statement)

References 85 publications

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“…Motoneurons express Z + agrin while muscle cells do not. Zagrin has also functions: it can modulate AChR phosphorylation 91 , stimulate AChR gene expression 92,93 and in certain conditions, induce AChR clustering 60,94,95 . Zagrin can bind myotube cell surface proteins, such as neural cell adhesion molecule, α-dystroglycan, laminins and integrins 28,[96][97][98][99] .…”

Section: Discussionmentioning

confidence: 99%

A link between agrin signalling and Cav3.2 at the neuromuscular junction in spinal muscular atrophy

Delers

Sapaly

Salman

et al. 2022

Sci Rep

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SMN protein deficiency causes motoneuron disease spinal muscular atrophy (SMA). SMN-based therapies improve patient motor symptoms to variable degrees. An early hallmark of SMA is the perturbation of the neuromuscular junction (NMJ), a synapse between a motoneuron and muscle cell. NMJ formation depends on acetylcholine receptor (AChR) clustering triggered by agrin and its co-receptors lipoprotein receptor-related protein 4 (LRP4) and transmembrane muscle-specific kinase (MuSK) signalling pathway. We have previously shown that flunarizine improves NMJs in SMA model mice, but the mechanisms remain elusive. We show here that flunarizine promotes AChR clustering in cell-autonomous, dose- and agrin-dependent manners in C2C12 myotubes. This is associated with an increase in protein levels of LRP4, integrin-beta-1 and alpha-dystroglycan, three agrin co-receptors. Furthermore, flunarizine enhances MuSK interaction with integrin-beta-1 and phosphotyrosines. Moreover, the drug acts on the expression and splicing of Agrn and Cacna1h genes in a muscle-specific manner. We reveal that the Cacna1h encoded protein Cav3.2 closely associates in vitro with the agrin co-receptor LRP4. In vivo, it is enriched nearby NMJs during neonatal development and the drug increases this immunolabelling in SMA muscles. Thus, flunarizine modulates key players of the NMJ and identifies Cav3.2 as a new protein involved in the NMJ biology.

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