Munc18

Introduction to Munc18

Synaptic transmission of neuronal information is regulated by a series of key proteins, among which mammalian uncoordinated 18 (Munc18) is one class of the important proteins for synaptic membrane fusion. Munc18, also known as syntaxin-binding protein, is a member of the Sec1/Munc18-like (SM) protein superfamily, a class of highly conserved proteins playing indispensable regulatory actions in the vesicle fusion of eukaryotic cells. Human Munc18 contains 6 homologous proteins: Munc18-1, Munc18-2, Munc18-3, Munc18-4, Munc18-5, and Munc18-6, which have been identified as critical regulators for exocytosis of neurons and neuroendocrine cells.

Mechanism of Munc18 in Neuron Exocytosis

Munc-18 proteins, especially Munc18-1, exert an essential role in intracellular membrane fusion. Each Munc-18 protein is specialized for a single fusion or vesicle trafficking step. Almost all intracellular membrane fusion in the secretory pathway is controlled by soluble N-ethylmaleimide-sensitive factor attachment protein receptors (SNAREs). The mechanisms of Munc-18 proteins in vesicle docking, intracellular membrane fusion, and neuronal exocytosis have been inferred to be involved in the interaction with the SNARE complex.

• Munc-18-1 binds to the closed conformations of the syntaxin-1, the core protein of SNARE, inhibiting the assembly of the SNARE complex and thereby regulating neurotransmitter transmission.
• With the help of Munc13-1 opening the syntaxin-1 closed conformation, Munc-18-1 is translocated to the closed conformations of the syntaxin-1. Both Munc13-1 and Munc-18-1 coordinate the assembly of the target membrane of SNARE, and Munc13-1 connects synaptic vesicles with presynaptic membrane fusion.
• Munc-18-1 also stabilizes the formed trans-SNARE complex and prevents the dissociation of the SNARE complex.
• It also has been demonstrated that Munc-18-1 interacts with the C-terminus of synaptobrevin, another critical SNARE protein responsible for the membrane fusion in exocytosis, affecting the formation of the SNARE complex.
• The phosphorylation of Munc18-1 can transfer synaptic vesicles to the active regions, promoting synaptic transmission and neurotransmitter release.

Fig.1 Munc18-1regulates neurotransmitter transmission by interacting with the SNARE complex. (Tang, 2021)

Diseases Related to Munc18 Abnormality

Munc18 are critical regulatory proteins in neuron exocytosis and neurotransmitter transmission, the mutation or abnormal expression of which results in a series of neurological diseases. The Munc18-1 deficiency caused by STXBP1 gene mutations, such as missense and splicing mutations, was closely related to epileptic encephalopathy. The regulatory activities in neurotransmitter transmission make Munc18-1 an important target in the pathogenesis of a variety of neurodegenerative diseases, including Parkinson's disease and Alzheimer's disease. Additionally, Munc18-1 deficiency also is implicated in other neurological disorders, such as schizophrenia, multiple sclerosis, Autism, and so forth.

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Reference

1. Tanf, F.J; et al. Role of Munc18-1 in the biological functions and pathogenesis of neurological disorders. Molecular Medicine Reports. 2021, 23(3): 198.