PUBLICATION
The Beta-Adrenergic Agonist Salbutamol Modulates Neuromuscular Junction Formation in Zebrafish Models of Human Myasthenic Syndromes
- Authors
- McMacken, G., Cox, D., Roos, A., Müller, J., Whittaker, R., Lochmüller, H.
- ID
- ZDB-PUB-180223-45
- Date
- 2018
- Source
- Human molecular genetics 27(9): 1556-1564 (Journal)
- Registered Authors
- Keywords
- none
- MeSH Terms
-
- Myasthenic Syndromes, Congenital*
- Zebrafish
- Signal Transduction/drug effects
- Humans
- Neuromuscular Junction/drug effects*
- Fluorescent Antibody Technique
- Muscle Proteins/genetics
- Muscle Proteins/metabolism
- Albuterol/pharmacology*
- Colforsin/pharmacology
- Adrenergic beta-Agonists/pharmacology*
- Animals
- PubMed
- 29462491 Full text @ Hum. Mol. Genet.
Citation
McMacken, G., Cox, D., Roos, A., Müller, J., Whittaker, R., Lochmüller, H. (2018) The Beta-Adrenergic Agonist Salbutamol Modulates Neuromuscular Junction Formation in Zebrafish Models of Human Myasthenic Syndromes. Human molecular genetics. 27(9):1556-1564.
Abstract
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 ?2 adrenergic agonist salbutamol and the ? and ? 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 ?2 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 ?2 adrenoceptors and via a cAMP-dependent pathway.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping