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Beschreibung

Protein unc-13 homolog A (UniProt: Q62768, also known as Munc13-1) is encoded by the Unc13a (also known as Unc13h1) gene (Gene ID: 64829) in rat. Munc13-1 is a large multifunctional peripheral membrane protein that is essential for synaptic vesicle fusion and neurotransmitter release. It is expressed in brain, with highest levels observed in the olfactory bulb, striatum, cerebral cortex, hippocampus, and cerebellum. Some expression has also been reported in pancreatic islet cells. Munc13-1 is involved in neurotransmitter release by acting in synaptic vesicle priming prior to vesicle fusion and also participates in the activity-dependent refilling of readily releasable vesicle pool. It contains a variable N-terminal region that contains a C2A domain and a calmodulin-binding region (CaMb) and a conserved C-terminal region that contains the C1, C2B, MUN and C2C domains. The C2A domain can form either a homodimer or a heterodimer with RIMs and provides a switch that controls neurotransmitter release and couples exocytosis to diverse forms of Rab3- and RIM-dependent presynaptic plasticity. The CaMb region is reported to mediate Ca2+-dependent short-term plasticity. The C1 domain mediates diacylglycerol and phorbol ester-dependent potentiation of release and the C2B domain acts as a Ca2+- and PIP2-dependent modulator of short-term plasticity. The MUN domain is highly elongated and is essential for opening syntaxin-1. In the presynaptic terminal, Munc13-1 is shown to form multiple and discrete supramolecular self-assemblies that serve as independent vesicular release sites by recruiting syntaxin-1. At the synaptic contacts in the active zone, Munc13-1 is essential for the formation of the syntaxin-1/Munc18-1 complex. This supramolecular assembly provides open syntaxin-1 molecules for use in the formation of active SNARE complexes and thereby specifies the site for synaptic vesicle docking, priming, and release. Munc3-1 is shown to be essential for synaptic vesicle maturation in most excitatory/glutamatergic but not inhibitory/GABA-mediated synapses. (Ref.: Quade, B., et al. (2019). eLife 8, e42806, Sakamoto, H., et al. (2018). Nat. Neurosci. 21(1), 41-49).