Dok-7 is a non-catalytic cytoplasmic adaptor protein that is expressed specifically in muscle and is essential for the formation of neuromuscular synapses. Further, Dok-7 contains

pleckstrin homology Pleckstrin homology domain (PH domain) or (PHIP) is a protein domain of approximately 120 amino acids that occurs in a wide range of proteins involved in intracellular signaling or as constituents of the cytoskeleton. This domain can bind phospha ...

(PH) and phosphotyrosine-binding (PTB) domains that are critical for Dok-7 function. Finally, mutations in Dok-7 are commonly found in patients with limb-girdle congenital myasthenia.

Dok-7 regulates neuromuscular synapse formation by activating MuSK

The formation of

neuromuscular synapse A neuromuscular junction (or myoneural junction) is a chemical synapse between a motor neuron and a muscle fiber. It allows the motor neuron to transmit a signal to the muscle fiber, causing muscle contraction. Muscles require innervation t ...

s requires the muscle-specific receptor tyrosine kinase (MuSK). In mice genetically mutant for MuSK,

acetylcholine receptor An acetylcholine receptor (abbreviated AChR) is an integral membrane protein that responds to the binding of acetylcholine, a neurotransmitter. Classification Like other transmembrane receptors, acetylcholine receptors are classified according ...

s (AChRs) fail to cluster and

motor neuron A motor neuron (or motoneuron or efferent neuron) is a neuron whose cell body is located in the motor cortex, brainstem or the spinal cord, and whose axon (fiber) projects to the spinal cord or outside of the spinal cord to directly or indirectl ...

s fail to differentiate. Because Dok-7 mutant mice are indistinguishable from MuSK mutant mice, these observations suggest Dok-7 might regulate MuSK activation. Indeed, Dok-7 binds phosphorylated MuSK and activates MuSK in purified protein preparations and in muscle in-vivo by transgenic overexpression. Furthermore, the nerve-derived organizing factor

agrin Agrin is a large proteoglycan whose best-characterised role is in the development of the neuromuscular junction during embryogenesis. Agrin is named based on its involvement in the aggregation of acetylcholine receptors during synaptogenesis. I ...

fails to stimulate MuSK activation in muscle cells genetically null for Dok-7. Thus, Dok-7 is both necessary and sufficient for the activation of MuSK.

Dok-7 signaling

The requirement for

MuSK Musk (Persian: مشک, ''Mushk'') is a class of aromatic substances commonly used as base notes in perfumery. They include glandular secretions from animals such as the musk deer, numerous plants emitting similar fragrances, and artificial sub ...

in the formation of the NMJ was primarily demonstrated by mouse "knockout" studies. In mice which are deficient for either agrin or MuSK, the

neuromuscular junction A neuromuscular junction (or myoneural junction) is a chemical synapse between a motor neuron and a muscle fiber. It allows the motor neuron to transmit a signal to the muscle fiber, causing muscle contraction. Muscles require innervation to ...

does not form. Upon activation by its ligand

, MuSK signals via the proteins called Dok-7 and

rapsyn 43 kDa receptor-associated protein of the synapse (rapsyn) is a protein that in humans is encoded by the ''RAPSN'' gene. Function This protein belongs to a family of proteins that are receptor associated proteins of the synapse. It contains a ...

, to induce "clustering" of acetylcholine receptors (

AChR An acetylcholine receptor (abbreviated AChR) is an integral membrane protein that responds to the binding of acetylcholine, a neurotransmitter. Classification Like other transmembrane receptors, acetylcholine receptors are classified according ...

). Cell signaling downstream of MuSK requires Dok-7. Mice which lack this protein fail to develop endplates. Further, forced expression of Dok-7 induces the tyrosine phosphorylation, and thus the activation of MuSK. Dok-7 interacts with MuSK by way of protein "domain" called a "

PTB domain In molecular biology, Phosphotyrosine-binding domains are protein domains which bind to phosphotyrosine. The phosphotyrosine-binding domain (PTB, also phosphotyrosine-interaction or PI domain) in the protein tensin tends to be found at the C-te ...

." In addition to the

, MuSK, and Dok-7 other proteins are then gathered, to form the endplate to the neuromuscular junction. The nerve terminates onto the endplate, forming the neuromuscular junction—a structure which is required to transmit nerve impulses to the muscle, and thus initiating muscle contraction.

Congenital Myasthenia Syndrome

Homozygous mutation of Dok-7 is responsible for a form of

congenital myasthenic syndrome Congenital myasthenic syndrome (CMS) is an inherited neuromuscular disorder caused by defects of several types at the neuromuscular junction. The effects of the disease are similar to Lambert-Eaton Syndrome and myasthenia gravis, the difference ...

(CMS) that is unique among disorders in this category because it affects muscles in the limbs and trunk but mostly spares the face, eyes, and functions of the mouth and pharynx (chewing, swallowing and speech).

Salbutamol Salbutamol, also known as albuterol and sold under the brand name Ventolin among others, is a medication that opens up the medium and large airways in the lungs. It is a short-acting β2 adrenergic receptor agonist which works by causing rel ...

can be effective in relieving CMS symptoms attributable to Dok-7 mutations.

References

* * * * * * *{{cite journal , vauthors=Palace J, Lashley D, Newsom-Davis J , title=Clinical features of the DOK7 neuromuscular junction synaptopathy , journal=Brain , volume=130 , issue=Pt 6 , pages=1507–15 , date=Jun 2007 , pmid=17452375 , doi=10.1093/brain/awm072 , display-authors=etal, citeseerx=10.1.1.547.7662 Developmental neuroscience Proteins