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Endocannabinoid signalling mediated by cannabinoid receptor 1 (CB1R, also known as CNR1) is critical for homeostatic neuromodulation of both excitatory and inhibitory synapses. This requires highly polarised axonal surface expression of CB1R, but how this is achieved remains unclear. We previously reported that the α-helical H9 domain in the intracellular C terminus of CB1R contributes to axonal surface expression by an unknown mechanism. Here, we show in rat primary neuronal cultures that the H9 domain binds to the endocytic adaptor protein SGIP1 to promote CB1R expression in the axonal membrane. Overexpression of SGIP1 increases CB1R axonal surface localisation but has no effect on CB1R lacking the H9 domain (CB1RΔH9). Conversely, SGIP1 knockdown reduces axonal surface expression of CB1R but does not affect CB1RΔH9. Furthermore, SGIP1 knockdown diminishes CB1R-mediated inhibition of presynaptic Ca2+ influx in response to neuronal activity. Taken together, these data advance mechanistic understanding of endocannabinoid signalling by demonstrating that SGIP1 interaction with the H9 domain underpins axonal CB1R surface expression to regulate presynaptic responsiveness. [ABSTRACT FROM AUTHOR]

The distribution and magnitude of forces driving lithospheric deformation in the India‐Eurasia collision zone have been debated over many decades. Here we test a two‐dimensional (2‐D) Thin Viscous Shell approach that has been adapted to explicitly account for displacement on major faults and investigate the impact of lateral variations in depth‐averaged lithospheric strength. We present a suite of dynamic models to explain the key features from new high‐resolution Sentinel‐1 Interferometric Synthetic Aperture Radar as well as Global Navigation Satellite System velocities. Comparisons between calculated and geodetically observed velocity and strain rate fields indicate: (a) internal buoyancy forces from Gravitational Potential Energy acting on a relatively weak region of highest topography (>2,000 m) contribute to dilatation of the high plateau and contraction on the margins; (b) a weak central Tibetan Plateau (∼1021 Pa s compared to far‐field depth‐averaged effective viscosity of at least 1022–1023 Pa s) is required to explain the observed long‐wavelength eastward velocity variation; (c) localized displacement on fault systems enables strain concentration and clockwise rotation around the Eastern Himalayan Syntaxis. We discuss the tectonic implications for rheology of the lithosphere, distribution of geodetic strain, and partitioning of active faulting and seismicity. Plain Language Summary: The collision of the Indian Plate with Eurasia has created the Tibetan Plateau, one of the largest deforming regions in the continents. The mode of deformation has been a focus for heated debate and has inspired two contrasting tectonic models: (a) The deformation is localized on major faults separating "blocks" or (b) the strain is distributed throughout a "continuum." We approximate the India‐Eurasia collision by treating the continent as a thin viscous shell with regional variations in strength, explicitly accounting for displacements on selected major faults. We present a suite of models to explain the key features of new geodetic measurements from satellites. The best‐fit model involves a weak Tibetan Plateau, a particularly weaker central plateau, and four strong regions outside the plateau, and allows displacements on major faults. This represents the deformation field of the India‐Eurasia collision zone as a combination of continuous distributed deformation and focused strain on major faults. Key Points: A suite of faulted viscous shell models testing key parameters explain new observations from geodesy for the India‐Asia collisionThe India‐Asia collision is explained by the balance between buoyancy and boundary forces, slip on faults, and internal strength variationsCentral Tibetan Plateau has a vertically‐averaged effective viscosity of ∼1021 Pa s, 1–2 orders lower than the surrounding area [ABSTRACT FROM AUTHOR]

In the continents, the importance of earthquakes that occur away from major block‐bounding faults is still debated. The 21 May 2021 MW ∼ 7.4 Maduo earthquake occurred on a secondary fault away from previously‐identified major block boundaries. Here we use 7 years of Sentinel‐1 Interferometric Synthetic Aperture Radar (InSAR) time series (between October 2014 and November 2021) to determine the distribution of coseismic slip and early postseismic afterslip following the Maduo earthquake, and the preceding interseismic strain accumulation. We devised a 13‐segment 3‐D fault geometry constrained by the SAR range offsets and the distribution of relocated aftershocks and used a Bayesian method incorporating von Karman regularization to solve for coseismic slip and afterslip models. We also used teleseismic waveforms as a standalone inversion to show the rupture evolution in space and time during the earthquake, finding that it propagates bilaterally with three notable rupture episodes. Our preferred coseismic self‐similar slip model shows a moderate shallow slip deficit, with the majority of moment release occurring in the depth interval of 1–10 km. The coseismic slip deficit is taken up in part by afterslip at shallow (<4 km) depths that grows linearly with time during the first ∼6 months, and at >10 km depths where afterslip grows logarithmically with time. We suggest that this heterogeneity is likely controlled by spatial variations in fault friction related to lithology. We discuss the implications for seismic hazard away from major tectonic block boundaries in light of our observations of the earthquake cycle on this intrablock fault. Plain Language Summary: Collision between the Indian and Eurasian plates has created the largest deforming region on the planet. Part of the resultant deformation is accommodated by movements on block‐bounding faults where major earthquakes usually occur. A large earthquake ruptured a slow‐moving fault away from the major pre‐identified block boundaries on 21 May 2021. We used 7 years of satellite radar images to measure the deformation that occurred before, during, and after the earthquake. We also used seismic observations to investigate the temporal evolution of the earthquake rupture. Our model agrees with the results from field mapping. Postseismic deformation at shallow and deep depths shows different temporally varying behavior, which is likely caused by the frictional properties of the fault associated with different physical characteristics of rocks. The causative fault was accumulating relatively subtle strain before the earthquake. We observed the strain being localized on one of the faults in the block interior, highlighting elevated earthquake potential in the future. Key Points: We present the earthquake cycle deformation for the 2021 Maduo earthquake from Sentinel‐1 Interferometric Synthetic Aperture Radar and teleseismic waveformsCoseismic slip deficit is taken up by shallow and deep afterslip with different temporal behavior; this may be controlled by lithologyInterseismic strain observed in the interior of a mapped tectonic block highlights importance of seismic hazard away from block boundaries [ABSTRACT FROM AUTHOR]

ATP-sensitive potassium ([K.sub.ATP]) channels are composed of four pore-forming Kir6.2 subunits and four regulatory SUR1 subunits. Binding of ATP to Kir6.2 leads to inhibition of channel activity. Because there are four subunits and thus four ATP-binding sites, four binding events are possible. ATP binds to both the open and closed states of the channel and produces a decrease in the mean open time, a reduction in the mean burst duration, and an increase in the frequency and duration of the interburst closed states. Here, we investigate the mechanism of interaction of ATP with the open state of the channel by analyzing the single-channel kinetics of concatenated Kir6.2 tetramers containing from zero to four mutated Kir6.2 subunits that possess an impaired ATP-binding site. We show that the ATP-dependent decrease in the mean burst duration is well described by a Monod-Wyman-Changeux model in which channel closing is produced by all four subunits acting in a single concerted step. The data are inconsistent with a Hodgkin-Huxley model (four independent steps) or a dimer model (two independent dimers). When the channel is open, ATP binds to a single ATP-binding site with a dissociation constant of 300 [micro]M.

The phosphorylation targets that mediate the enhancement of exocytosis by PKC are unknown. PKC phosporylates the SNARE protein SNAP-25 at Ser-187. We expressed mutants of SNAP-25 using the Semliki Forest Virus system in bovine adrenal chromaffin cells and then directly measured the [Ca.sup.2+] dependence of exocytosis using photorelease of caged [Ca.sup.2+] together with patch-clamp capacitance measurements. A flash of UV light used to elevate [[Ca.sup.2+].sub.i] to several [micro]M and release the highly [Ca.sup.2+]-sensitive pool (HCSP) of vesicles was followed by a train of depolarizing pulses to elicit exocytosis from the less [Ca.sup.2+]-sensitive readily releasable pool (RRP) of vesicles. Carbon fiber amperometry confirmed that the amount and kinetics of catecholamine release from individual granules were similar for the two phases of exocytosis. Mimicking PKC phosphorylation with expression of the S187E SNAP-25 mutant resulted in an approximately threefold increase in the HCSP, whereas the response to depolarization increased only 1.5-fold. The phosphomimetic S187D mutation resulted in an ~1.5-fold increase in the HCSP but a 30% smaller response to depolarization. In vitro binding assays with recombinant SNARE proteins were performed to examine shifts in protein-protein binding that may promote the highly [Ca.sup.2+]-sensitive state. The S187E mutant exhibited increased binding to syntaxin but decreased [Ca.sup.2+]-independent binding to synaptotagmin I. Mimicking phosphorylation of the putative PKA phosphorylation site of SNAP-25 with the TI38E mutation decreased binding to both syntaxin and synaptotagmin I in vitro. Expressing the T138E/S187E double mutant in chromaffin cells demonstrated that enhancing the size of the HCSP correlates with an increase in SNAP-25 binding to syntaxin in vitro, but not with [Ca.sup.2+]-independent binding of SNAP-25 to synaptotagmin I. Our results support the hypothesis that exocytosis triggered by lower [Ca.sup.2+] concentrations (from the HCSP) occurs by different molecular mechanisms than exocytosis triggered by higher [Ca.sup.2+] levels.

Gene deletion analysis show that CheR(sub)2 and CheB(sub)1 are involved in chemotaxis of Rhodobacter sphaeroides. Their interaction with methyl-accepting chemotaxis proteins indicate a role for methyl-dependent chemotaxis.

The t‐soluble NSF‐attachment protein receptor protein Syntaxin‐1a (Stx‐1a) is abundantly expressed at pre‐synaptic terminals where it plays a critical role in the exocytosis of neurotransmitter‐containing synaptic vesicles. Stx‐1a is phosphorylated by Casein kinase 2α (CK2α) at Ser14, which has been proposed to regulate the interaction of Stx‐1a and Munc‐18 to control of synaptic vesicle priming. However, the role of CK2α in synaptic vesicle dynamics remains unclear. Here, we show that CK2α over‐expression reduces evoked synaptic vesicle release. Furthermore, shRNA‐mediated knockdown of CK2α in primary hippocampal neurons strongly enhanced vesicle exocytosis from the reserve pool, with no effect on the readily releasable pool of primed vesicles. In neurons in which endogenous Stx‐1a was knocked down and replaced with a CK2α phosphorylation‐deficient mutant, Stx‐1a(D17A), vesicle exocytosis was also increased. These results reveal a previously unsuspected role of CK2α phosphorylation in specifically regulating the reserve synaptic vesicle pool, without changing the kinetics of release from the readily releasable pool. [ABSTRACT FROM AUTHOR]