Building the synapse

Building the synapse

August 1, 2006

The neuromuscular synapse, whereby neurons control muscle, requires the neurotransmitter acetylcholine. Muscle-specific receptor kinase (MuSK) ensures acetylcholine receptors on the muscle are densely clustered. A motif on MuSK critical for its function targets a phosphotyrosine-binding domain, but the identity of the protein bearing this domain had until recently remained elusive.

Scientists at Tokyo Medical and Dental University and their colleagues were searching databases for new members of the Dok protein family, which have phosphotyrosine-binding domains, when they came across Dok-7. They found that Dok-7 is expressed preferentially in skeletal muscle and the heart, and mice lacking it fail to form acetylcholine receptor clusters and neuromuscular synapses.

This research "discovered the protein that allows MuSK to work," says Faculty of 1000 member Steven Burden at New York University.

The glycoprotein agrin can activate MuSK, but one mystery concerns how acetylcholine receptors that depend on MuSK can form even without agrin, suggesting another element at work. While the researchers showed Dok-7 acts downstream of activated MuSK, in vitro data suggest that Dok-7 may act upstream of it as well to help activate MuSK in the absence of agrin, Burden speculates. If so, he adds, "there must be some way to regulate that feedback loop that can otherwise run out of control."

1. K. Okada et al., "The muscle protein Dok-7 is essential for neuromuscular synaptogenesis," Science, 312:1802-5, June 23, 2006.

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