Disease relevance of UNC13B

• Human munc13 is a diacylglycerol receptor that induces apoptosis and may contribute to renal cell injury in hyperglycemia [1].

High impact information on UNC13B

• This region contains hMunc13-4, a member of the Munc13 family of proteins involved in vesicle priming function [2].
• A second DGK-1-independent mechanism is revealed by the ability of a Rho inhibitor (C3 transferase) to decrease levels of release even in the absence of DGK-1; this pathway is independent of UNC-13 accumulation at release sites [3].
• Our data suggest that the ternary Rab3/RIM/Munc13 interaction approximates synaptic vesicles to the priming machinery, providing a substrate for presynaptic plasticity [4].
• Munc13 binding is mediated by the alpha-RIM zinc-finger domain [4].
• 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 [5].

Biological context of UNC13B

• We conclude that both the diacylglycerol-induced translocation and the apoptosis represent functional activity of hmunc13 [1].
• We hypothesize that this novel Ca(2+)-induced activity of DOC2B functions synergistically with diacylglycerol-induced Munc13 binding to enhance exocytosis during episodes of high secretory activity [6].
• 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 [7].
• 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 [8].
• The GA search demonstrates that the parameters that control the kinetics of exocytosis are the rate constants of the steps downstream to synaptotagmin binding, and that the equilibrium constant of the binding of calcium to Munc13 controls the calcium-dependent priming process [9].

Anatomical context of UNC13B

• Diacylglycerol induces translocation of the vesicle priming factor Munc13 and association of the secretory vesicle protein DOC2B to the membrane [6].
• To do this, we have investigated the subcellular localization of hmunc13 in a transiently transfected renal cell line, opossum kidney cells [1].
• We have previously shown that human munc13 (hmunc13) is up-regulated by hyperglycemia under in vitro conditions in human mesangial cell cultures [1].
• These data suggest that Noc2 is involved in the recruitment of secretory granules at the plasma membrane possibly via the interaction with Munc13 [10].
• Because Rab34 is known to regulate intracellular lysosome positioning, we propose that hmunc13 serves as an effector of Rab34, mediating lysosome-Golgi trafficking [11].

Associations of UNC13B with chemical compounds

• In addition, cells transfected with hmunc13 demonstrate apoptosis after treatment with phorbol ester, but cells transfected with an hmunc13 deletion mutant in which the diacylglycerol (C1) binding domain is absent exhibit no change in intracellular distribution and no induction of apoptosis in the presence of phorbol ester stimulation [1].
• Doc2 has one Munc13-interacting domain at the N-terminal region and two C2-like domains interacting with Ca2+ and phospholipid at the C-terminal region [12].
• By using relative RT-PCR and Northern blot, we have confirmed that expression of hmunc13 in MC is up-regulated by high D-glucose treatment [13].
• In presynaptic nerve termini, RIM1alpha interacts with a series of presynaptic proteins, including the synaptic vesicle GTPase Rab3 and the active zone proteins Munc13, liprins and ELKS (a protein rich in glutamate, leucine, lysine and serine) [14].

Regulatory relationships of UNC13B

• Furthermore, munc13 expressed with syntaxin1A and munc18 promoted redistribution of a cytosolic SNAP25 mutant to the membrane, a result indicative of syntaxin1A-SNAP25 SNARE pairing [15].

Other interactions of UNC13B

• 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 [16].
• Protein-protein binding studies revealed that Noc2 is a potential partner of Munc13, a component of the machinery that controls vesicle priming and insulin exocytosis [10].
• Deletion of munc homolgy domain (MHD)-2, eliminated the hmunc13/Rab34 interaction [11].
• At the neuronal synapse, munc13 as well as munc18 control SNARE complex assembly [17].
• DAG then activates UNC-13 and synaptobrevin, two proteins which play an important role in presynaptic vesicle-functioning [18].

Analytical, diagnostic and therapeutic context of UNC13B

• 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 [7].

References