Defining the structural relationship between kainate-receptor deactivation and desensitization

nature structural & molecular biology advance online publication a r t i c l e s Structural and functional biologists have long sought to understand the mechanisms by which LGICs respond to small chemical ligands and modulators. Seminal work established the general principle that LGICs not only are activated by biologically derived molecules, such as the neurotransmitter acetylcholine 1 , but also are inactivated by prolonged exposure to these molecules through a process universally known as desensitization 2 . Since this work, almost all LGICs have been shown to desensitize. For example, desensitization is thought to shape signaling within the vertebrate central nervous system by affecting the fast chemical transmission mediated by iGluRs along with GABA A and glycine receptors 3 . From all of this work, it has been concluded that the conformational events that lead to the occurrence of deactivation and the onset of desensitization are governed by the physicochemical properties of the bound ligand 4 . In support of this, pioneering work on native AMPA-type iGluRs (AMPARs) has shown that even modest changes to the ligand structure have profound effects on the rates and degree of desensitization 5 . During the last decade, structural and functional analyses of LGICs have revealed that the molecular basis of channel gating may be quite distinct for different ion-channel families Here, we set out to study the molecular basis of KAR desensitization by evaluating mutants that are proposed to block it RESULTS KARs desensitize with or without prior channel activation To observe the microscopic behavior of KAR desensitization, we excised outside-out patches from transfected mammalian cells Desensitization is an important mechanism curtailing the activity of ligand-gated ion channels (LGICs). Although the structural basis of desensitization is not fully resolved, it is thought to be governed by physicochemical properties of bound ligands. Here, we show the importance of an allosteric cation-binding pocket in controlling transitions between activated and desensitized states of rat kainate-type (KAR) ionotropic glutamate receptors (iGluRs). Tethering a positive charge to this pocket sustains KAR activation, preventing desensitization, whereas mutations that disrupt cation binding eliminate channel gating. These different outcomes explain the structural distinction between deactivation and desensitization. Deactivation occurs when the ligand unbinds before the cation, whereas desensitization proceeds if a ligand is bound without cation pocket occupancy. This sequence of events is absent from AMPA-type iGluRs; thus, cations are identified as gatekeepers of KAR gating, a role unique among even closely related LGICs

Search for top and bottom squarks from gluino pair production in final states with missing transverse energy and at least three b-jets with the ATLAS detector

This letter reports the results of a search for top and bottom squarks from gluino pair production in 4. 7 fb -1 of pp collisions at √s =7 TeV using the ATLAS detector at the LHC. The search is performed in events with large missing transverse momentum and at least three jets identified as originating from a b-quark. Exclusion limits are presented for a variety of gluino-mediated models with gluino masses up to 1 TeV excluded. © 2012 CERN for the benefit of the ATLAS collaboration

Measurements of the Total and Differential Higgs Boson Production Cross Sections Combining the H??????? and H???ZZ*???4??? Decay Channels at s\sqrt{s}=8??????TeV with the ATLAS Detector

Measurements of the total and differential cross sections of Higgs boson production are performed using 20.3~fb$^{-1}$ of $pp$ collisions produced by the Large Hadron Collider at a center-of-mass energy of $\sqrt{s} = 8$ TeV and recorded by the ATLAS detector. Cross sections are obtained from measured $H \rightarrow \gamma \gamma$ and $H \rightarrow ZZ ^{*}\rightarrow 4\ell$ event yields, which are combined accounting for detector efficiencies, fiducial acceptances and branching fractions. Differential cross sections are reported as a function of Higgs boson transverse momentum, Higgs boson rapidity, number of jets in the event, and transverse momentum of the leading jet. The total production cross section is determined to be $\sigma_{pp \to H} = 33.0 \pm 5.3 \, ({\rm stat}) \pm 1.6 \, ({\rm sys}) \mathrm{pb}$. The measurements are compared to state-of-the-art predictions.Measurements of the total and differential cross sections of Higgs boson production are performed using 20.3  fb-1 of pp collisions produced by the Large Hadron Collider at a center-of-mass energy of s=8  TeV and recorded by the ATLAS detector. Cross sections are obtained from measured H→γγ and H→ZZ*→4ℓ event yields, which are combined accounting for detector efficiencies, fiducial acceptances, and branching fractions. Differential cross sections are reported as a function of Higgs boson transverse momentum, Higgs boson rapidity, number of jets in the event, and transverse momentum of the leading jet. The total production cross section is determined to be σpp→H=33.0±5.3 (stat)±1.6 (syst)  pb. The measurements are compared to state-of-the-art predictions.Measurements of the total and differential cross sections of Higgs boson production are performed using 20.3 fb$^{-1}$ of $pp$ collisions produced by the Large Hadron Collider at a center-of-mass energy of $\sqrt{s} = 8$ TeV and recorded by the ATLAS detector. Cross sections are obtained from measured $H \rightarrow \gamma \gamma$ and $H \rightarrow ZZ ^{*}\rightarrow 4\ell$ event yields, which are combined accounting for detector efficiencies, fiducial acceptances and branching fractions. Differential cross sections are reported as a function of Higgs boson transverse momentum, Higgs boson rapidity, number of jets in the event, and transverse momentum of the leading jet. The total production cross section is determined to be $\sigma_{pp \to H} = 33.0 \pm 5.3 \, ({\rm stat}) \pm 1.6 \, ({\rm sys}) \mathrm{pb}$. The measurements are compared to state-of-the-art predictions