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Hum Mol Genet. 2018 May 1;27(9):1556-1564. doi: 10.1093/hmg/ddy062.

The beta-adrenergic agonist salbutamol modulates neuromuscular junction formation in zebrafish models of human myasthenic syndromes.

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Institute of Genetic Medicine, The John Walton Muscular Dystrophy Research Centre, Newcastle University, International Centre for Life, Newcastle Upon Tyne NE1 3BZ, UK.
Tissue Omics Project Group, Biomedical Research Department, Leibniz-Institut für Analytische Wissenschaften-ISAS-e.V., 44227 Dortmund, Germany.
Institute of Genetic Medicine, Wellcome Trust Centre for Mitochondrial Research, Newcastle University, International Centre for Life, Newcastle Upon Tyne NE1 3BZ, UK.
Institute of Neuroscience, Newcastle University, Newcastle Upon Tyne NE1 7RU, UK.


Inherited defects of the neuromuscular junction (NMJ) comprise an increasingly diverse range of disorders, termed congenital myasthenic syndromes (CMS). Therapies acting on the sympathetic nervous system, including the selective β2 adrenergic agonist salbutamol and the α and β adrenergic agonist ephedrine, have become standard treatment for several types of CMS. However, the mechanism of the therapeutic effect of sympathomimetics in these disorders is not understood. Here, we examined the effect of salbutamol on NMJ development using zebrafish with deficiency of the key postsynaptic proteins Dok-7 and MuSK. Treatment with salbutamol reduced motility defects in zebrafish embryos and larvae. In addition, salbutamol lead to morphological improvement of postsynaptic acetycholine receptor (AChR) clustering and size of synaptic contacts in Dok-7-deficient zebrafish. In MuSK-deficient zebrafish, salbutamol treatment reduced motor axon pathfinding defects and partially restored the formation of aneural prepatterned AChRs. In addition, the effects of salbutamol treatment were prevented by pre-treatment with a selective β2 antagonist. Treatment with the cyclic adenosine monophosphate (cAMP) activator forskolin, replicated the effects of salbutamol treatment. These results suggest that sympathomimetics exert a direct effect on neuromuscular synaptogenesis and do so via β2 adrenoceptors and via a cAMP-dependent pathway.

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