Phorbolester-activated Munc13-1 and ubMunc13-2 exert opposing effects on dense-core vesicle secretion

Munc13 proteins are priming factors for SNARE-dependent exocytosis, which are activated by diacylglycerol (DAG)-binding to their C1-domain. Several Munc13 paralogs exist, but their differential roles are not well understood. We studied the interdependence of phorbolesters (DAG mimics) with Munc13-1 and ubMunc13-2 in mouse adrenal chromaffin cells. Although expression of either Munc13-1 or ubMunc13-2 stimulated secretion, phorbolester was only stimulatory for secretion when ubMunc13-2 expression dominated, but inhibitory when Munc13-1 dominated. Accordingly, phorbolester stimulated secretion in wildtype cells, or cells overexpressing ubMunc13-2, but inhibited secretion in Munc13-2/Unc13b knockout (KO) cells or in cells overexpressing Munc13-1. Phorbolester was more stimulatory in the Munc13-1/Unc13a KO than in WT littermates, showing that endogenous Munc13-1 limits the effects of phorbolester. Imaging showed that ubMunc13-2 traffics to the plasma membrane with a time-course matching Ca2+-dependent secretion, and trafficking is independent of Synaptotagmin-7 (Syt7). However, in the absence of Syt7, phorbolester became inhibitory for both Munc13-1 and ubMunc13-2-driven secretion, indicating that stimulatory phorbolester x Munc13-2 interaction depends on functional pairing with Syt7. Overall, DAG/phorbolester, ubMunc13-2 and Syt7 form a stimulatory triad for dense-core vesicle priming

Five-dimensional non-Lorentzian conformal field theories and their relation to six-dimensions

We study correlation functions in five-dimensional non-Lorentzian theories with an SU(1, 3) conformal symmetry. Examples of such theories have recently been obtained as Ω-deformed Yang-Mills Lagrangians arising from a null reduction of six-dimensional superconformal field theories on a conformally compactified Minkowski space. The correlators exhibit a rich structure with many novel properties compared to conventional correlators in Lorentzian conformal field theories. Moreover, identifying the instanton number with the Fourier mode number of the dimensional reduction offers a hope to formulate six-dimensional conformal field theories in terms of five-dimensional Lagrangian theories. To this end we show that the Fourier decompositions of six-dimensional correlation functions solve the Ward identities of the SU(1, 3) symmetry, although more general solutions are possible. Conversely we illustrate how one can reconstruct six-dimensional correlation functions from those of a five-dimensional theory, and do so explicitly at 2- and 3-points. We also show that, in a suitable decompactification limit Ω → 0, the correlation functions become those of the DLCQ description

Distinct modes of endocytotic presynaptic membrane and protein uptake at the calyx of Held terminal of rats and mice.

Neurotransmitter is released at synapses by fusion of synaptic vesicles with the plasma membrane. To sustain synaptic transmission, compensatory retrieval of membranes and vesicular proteins is essential. We combined capacitance measurements and pH-imaging via pH-sensitive vesicular protein marker (anti-synaptotagmin2-cypHer5E), and compared the retrieval kinetics of membranes and vesicular proteins at the calyx of Held synapse. Membrane and Syt2 were retrieved with a similar time course when slow endocytosis was elicited. When fast endocytosis was elicited, Syt2 was still retrieved together with the membrane, but endocytosed organelle re-acidification was slowed down, which provides strong evidence for two distinct endocytotic pathways. Strikingly, CaM inhibitors or the inhibition of the Ca2+-calmodulin-Munc13-1 signaling pathway only impaired the uptake of Syt2 while leaving membrane retrieval intact, indicating different recycling mechanisms for membranes and vesicle proteins. Our data identify a novel mechanism of stimulus-and Ca2+-dependent regulation of coordinated endocytosis of synaptic membranes and vesicle proteins

Munc13-1 is a Ca2+-phospholipid-dependent vesicle priming hub that shapes synaptic short-term plasticity and enables sustained neurotransmission

During ongoing presynaptic action potential (AP) firing, transmitter release is limited by the availability of release-ready synaptic vesicles (SVs). The rate of SV recruitment (SVR) to release sites is strongly upregu- lated at high AP frequencies to balance SV consumption. We show that Munc13-1—an essential SV priming protein—regulates SVR via a Ca2+-phospholipid-dependent mechanism. Using knockin mouse lines with point mutations in the Ca2+-phospholipid-binding C2B domain of Munc13-1, we demonstrate that abolishing Ca2+-phospholipid binding increases synaptic depression, slows recovery of synaptic strength after SV pool depletion, and reduces temporal fidelity of synaptic transmission, while increased Ca2+-phospholipid binding has the opposite effects. Thus, Ca2+-phospholipid binding to the Munc13-1-C2B domain accelerates SVR, reduces short-term synaptic depression, and increases the endurance and temporal fidelity of neurotrans- mission, demonstrating that Munc13-1 is a core vesicle priming hub that adjusts SV re-supply to demand

On the Fermionic Frequencies of Circular Strings

We revisit the semiclassical computation of the fluctuation spectrum around different circular string solutions in AdS_5xS^5 and AdS_4xCP^3, starting from the Green-Schwarz action. It has been known that the results for these frequencies obtained from the algebraic curve and from the worldsheet computations sometimes do not agree. In particular, different methods give different results for the half-integer shifts in the mode numbers of the frequencies. We find that these discrepancies can be removed if one carefully takes into account the transition matrices in the spin bundle over the target space.Comment: 13 pages, 1 figur

Superconformal M2-branes and generalized Jordan triple systems

Three-dimensional conformal theories with six supersymmetries and SU(4) R-symmetry describing stacks of M2-branes are here proposed to be related to generalized Jordan triple systems. Writing the four-index structure constants in an appropriate form, the Chern-Simons part of the action immediately suggests a connection to such triple systems. In contrast to the previously considered three-algebras, the additional structure of a generalized Jordan triple system is associated to a graded Lie algebra, which corresponds to an extension of the gauge group. In this note we show that the whole theory with six manifest supersymmetries can be naturally expressed in terms of such a graded Lie algebra. Also the BLG theory with eight supersymmetries is included as a special case.Comment: 15 pages, v2 and v3: minor corrections and clarifications, references added, v2: section 4 extended, v3: published versio

Photoswitchable diacylglycerols enable optical control of protein kinase C.

Increased levels of the second messenger lipid diacylglycerol (DAG) induce downstream signaling events including the translocation of C1-domain-containing proteins toward the plasma membrane. Here, we introduce three light-sensitive DAGs, termed PhoDAGs, which feature a photoswitchable acyl chain. The PhoDAGs are inactive in the dark and promote the translocation of proteins that feature C1 domains toward the plasma membrane upon a flash of UV-A light. This effect is quickly reversed after the termination of photostimulation or by irradiation with blue light, permitting the generation of oscillation patterns. Both protein kinase C and Munc13 can thus be put under optical control. PhoDAGs control vesicle release in excitable cells, such as mouse pancreatic islets and hippocampal neurons, and modulate synaptic transmission in Caenorhabditis elegans. As such, the PhoDAGs afford an unprecedented degree of spatiotemporal control and are broadly applicable tools to study DAG signaling

On the structure of k-Lie algebras

We show that the structure constants of $k$-Lie algebras, $k>3$, with a positive definite metric are the sum of the volume forms of orthogonal $k$-planes. This generalizes the result for $k=3$ in arXiv:0804.2662 and arXiv:0804.3078, and confirms a conjecture in math/0211170.Comment: 4 pages, minor changes and a reference adde

Tree-Level Formalism

We review two novel techniques used to calculate tree-level scattering amplitudes efficiently: MHV diagrams, and on-shell recursion relations. For the MHV diagrams, we consider applications to tree-level amplitudes and focus in particular on the N=4 supersymmetric formulation. We also briefly describe the derivation of loop amplitudes using MHV diagrams. For the recursion relations, after presenting their general proof, we discuss several applications to massless theories with and without supersymmetry, to theories with massive particles, and to graviton amplitudes in General Relativity. This article is an invited review for a special issue of Journal of Physics A devoted to "Scattering Amplitudes in Gauge Theories".Comment: 40 pages, 8 figures, invited review for a special issue of Journal of Physics A devoted to "Scattering Amplitudes in Gauge Theories", R. Roiban(ed), M. Spradlin(ed), A. Volovich(ed); v2: minor corrections, references adde