High impact information on UNC13A

• Moreover, the levels of Munc13-1 and ubMunc13-2 levels are decreased in RIM1alpha-deficient brain, and Munc13-1 is not properly enriched at active zones of mossy fiber terminals of the mouse hippocampus if RIM1alpha is absent [1].
• We identify a single point mutation in Munc13-1 and ubMunc13-2 (I121N) that, depending on the type of assay used, strongly perturbs or abolishes RIM1alpha binding in vitro and in cultured fibroblasts, and we demonstrate that RIM1alpha binding-deficient ubMunc13-2(I121) is not efficiently recruited to synapses [1].
• Members of the Munc13 protein family consisting of Munc13-1, -2, -3, and -4 were found to be absolutely required for this priming process . In the present study, we identified the minimal Munc13-1 domain that is responsible for its priming activity [2].
• Using Munc13-1 deletion constructs in an electrophysiological gain-of-function assay of chromaffin-granule secretion, we show that priming activity is mediated by the C-terminal residues 1100-1735 of Munc13-1, which contains both Munc13-homology domains and the C-terminal C2 domain [2].
• Identification of the minimal protein domain required for priming activity of Munc13-1 [2].

Biological context of UNC13A

• We show here that the active zone recruitment of Munc13 isoforms Munc13-1 and ubMunc13-2 is regulated by their binding to the Rab3A-interacting molecule RIM1alpha, a key determinant of long term potentiation of synaptic transmission at mossy fiber synapses in the hippocampus [1].
• These results suggest that ELKS is involved in Ca(2+)-dependent exocytosis from PC12 cells at least partly via the RIM2-Munc13-1 pathway [3].
• Indeed, Munc13-1 and ubMunc13-2 contain a conserved calmodulin (CaM) binding site and the Ca(2+)-dependent interaction of these Munc13 isoforms with CaM constitutes a molecular mechanism that transduces residual Ca(2+) signaling to the synaptic exocytotic machinery [4].
• Thus, neurosecretion involves two key processes: the docking of vesicles at the transmitter release site, a process that involves the scaffold protein RIM (Rab3A interacting molecule) and its binding partner Munc-13, and the subsequent gating of vesicle fusion by activation of the Ca2+ channels [5].
• In neurons, a Munc13-1 C(2)A-domain/RIM zinc-finger domain (ZF) heterodimer couples synaptic vesicle priming to presynaptic plasticity [6].

Anatomical context of UNC13A

• Priming by Munc13-1 appears to require its interaction with Syntaxin 1 because point mutants that do not bind Syntaxin 1 do not prime chromaffin granules [2].
• Due to their essential function in synaptic vesicle priming and in the modulation of synaptic strength, Munc13 proteins have emerged as key regulators of these adaptive mechanisms [4].

Associations of UNC13A with chemical compounds

• The 51-mer chimaerin C1 peptides showed potent PDBu binding, while the Unc13 and Munc13-1 C1 peptides without sufficient positive charges hardly bound PDBu [7].
• Pharmacological characterization showed that potentiation of exocytosis depended on the activation of PLC but not protein kinase C. Overexpression of wild-type Munc13-1 by adenoviral infection had no effect on histamine-induced potentiation per se, whereas DAG-insensitive Munc13-1(H567K) completely abolished it [8].

Physical interactions of UNC13A

• Potentiation of exocytosis by phospholipase C-coupled G-protein-coupled receptors requires the priming protein Munc13-1 [8].

Other interactions of UNC13A

• The cytomatrix at the AZ (CAZ)-associated protein CAST and its family member ELKS form a large molecular complex at the AZ and regulate neurotransmitter release by binding other AZ proteins including Bassoon, Piccolo, Munc13-1, and RIM1 [9].
• Furthermore, we affinity-purified a GTP-Rab27A-binding protein in platelets and identified it as Munc13-4, a homologue of Munc13-1 known as a priming factor for neurotransmitter release [10].
• X-ray diffraction studies guided by nuclear magnetic resonance (NMR) experiments reveal the crystal structures of the Munc13-1 C(2)A-domain homodimer and the Munc13-1 C(2)A-domain/RIM ZF heterodimer at 1.44 A and 1.78 A resolution, respectively [6].

Analytical, diagnostic and therapeutic context of UNC13A

• A PAL-based Ca(2+) titration assay revealed that all Munc13 isoforms can form a complex with CaM already at low Ca(2+) concentrations just above resting levels, underscoring the Ca(2+) sensor/effector function of this interaction in short-term synaptic plasticity phenomena [4].

References