Inhibition of synaptic transmission and G protein modulation by synthetic CaV2.2 Ca2+ channel peptides

Abstract: Modulation of presynaptic voltage-dependent Ca+ channels is a major means of controlling neurotransmitter release. The CaV 2.2 Ca2+ channel subunit contains several inhibitory interaction sites for Gβγ subunits, including the amino terminal (NT) and I–II loop. The NT and I–II loop have also been proposed to undergo a G protein-gated inhibitory interaction, whilst the NT itself has also been proposed to suppress CaV 2 channel activity. Here, we investigate the effects of an amino terminal (CaV 2.2[45–55]) ‘NT peptide’ and a I–II loop alpha interaction domain (CaV 2.2[377–393]) ‘AID peptide’ on synaptic transmission, Ca2+ channel activity and G protein modulation in superior cervical ganglion neurones (SCGNs). Presynaptic injection of NT or AID peptide into SCGN synapses inhibited synaptic transmission and also attenuated noradrenaline-induced G protein modulation. In isolated SCGNs, NT and AID peptides reduced whole-cell Ca2+ current amplitude, modified voltage dependence of Ca2+ channel activation and attenuated noradrenaline-induced G protein modulation. Co-application of NT and AID peptide negated inhibitory actions. Together, these data favour direct peptide interaction with presynaptic Ca2+ channels, with effects on current amplitude and gating representing likely mechanisms responsible for inhibition of synaptic transmission. Mutations to residues reported as determinants of Ca2+ channel function within the NT peptide negated inhibitory effects on synaptic transmission, Ca2+ current amplitude and gating and G protein modulation. A mutation within the proposed QXXER motif for G protein modulation did not abolish inhibitory effects of the AID peptide. This study suggests that the CaV 2.2 amino terminal and I–II loop contribute molecular determinants for Ca2+ channel function; the data favour a direct interaction of peptides with Ca2+ channels to inhibit synaptic transmission and attenuate G protein modulation. Non-technical summary: Nerve cells (neurones) in the body communicate with each other by releasing chemicals (neurotransmitters) which act on proteins called receptors. An important group of receptors (called G protein coupled receptors, GPCRs) regulate the release of neurotransmitters by an action on the ion channels that let calcium into the cell. Here, we show for the first time that small peptides based on specific regions of calcium ion channels involved in GPCR signalling can themselves inhibit nerve cell communication. We show that these peptides act directly on calcium channels to make them more difficult to open and thus reduce calcium influx into native neurones. These peptides also reduce GPCR-mediated signalling. This work is important in increasing our knowledge about modulation of the calcium ion channel protein; such knowledge may help in the development of drugs to prevent signalling in pathways such as those involved in pain perception

Cell biology:Collagen secretion explained

Cells package proteins into vesicles for secretion to the extracellular milieu. A study shows that an enzyme modifies the packaging machinery to encapsulate unusually large proteins such as collagen

Does Every Quasar Harbor A Blazar?

Assuming there is a blazar type continuum in every radio-loud quasar, we find that the free-free heating due to the beamed infrared continuum can greatly enhance collisionally excited lines, and thus explain the stronger CIV $\lambda$1549 line emission observed in radio loud quasars. We further predict that the CIV line should show variability {\it not} associated with observed continuum or Ly$\alpha$ variability.Comment: 15 pages, 3 figures; to appear in Astrophys. J. Let

From quantum fusiliers to high-performance networks

Our objective was to design a quantum repeater capable of achieving one million entangled pairs per second over a distance of 1000km. We failed, but not by much. In this letter we will describe the series of developments that permitted us to approach our goal. We will describe a mechanism that permits the creation of entanglement between two qubits, connected by fibre, with probability arbitrarily close to one and in constant time. This mechanism may be extended to ensure that the entanglement has high fidelity without compromising these properties. Finally, we describe how this may be used to construct a quantum repeater that is capable of creating a linear quantum network connecting two distant qubits with high fidelity. The creation rate is shown to be a function of the maximum distance between two adjacent quantum repeaters.Comment: 2 figures, Comments welcom

The Stokes Phenomenon and Quantum Tunneling for de Sitter Radiation in Nonstationary Coordinates

We study quantum tunneling for the de Sitter radiation in the planar coordinates and global coordinates, which are nonstationary coordinates and describe the expanding geometry. Using the phase-integral approximation for the Hamilton-Jacobi action in the complex plane of time, we obtain the particle-production rate in both coordinates and derive the additional sinusoidal factor depending on the dimensionality of spacetime and the quantum number for spherical harmonics in the global coordinates. This approach resolves the factor of two problem in the tunneling method.Comment: LaTex 10 pages, no figur

Defect Formation and Critical Dynamics in the Early Universe

We study the nonequilibrium dynamics leading to the formation of topological defects in a symmetry-breaking phase transition of a quantum scalar field with \lambda\Phi^4 self-interaction in a spatially flat, radiation-dominated Friedmann-Robertson-Walker Universe. The quantum field is initially in a finite-temperature symmetry-restored state and the phase transition develops as the Universe expands and cools. We present a first-principles, microscopic approach in which the nonperturbative, nonequilibrium dynamics of the quantum field is derived from the two-loop, two-particle-irreducible closed-time-path effective action. We numerically solve the dynamical equations for the two-point function and we identify signatures of topological defects in the infrared portion of the momentum-space power spectrum. We find that the density of topological defects formed after the phase transition scales as a power law with the expansion rate of the Universe. We calculate the equilibrium critical exponents of the correlation length and relaxation time for this model and show that the power law exponent of the defect density, for both overdamped and underdamped evolution, is in good agreement with the "freeze-out" scenario of Zurek. We introduce an analytic dynamical model, valid near the critical point, that exhibits the same power law scaling of the defect density with the quench rate. By incorporating the realistic quench of the expanding Universe, our approach illuminates the dynamical mechanisms important for topological defect formation. The observed power law scaling of the defect density with the quench rate, observered here in a quantum field theory context, provides evidence for the "freeze-out" scenario in three spatial dimensions.Comment: 31 pages, RevTex, 8 figures in EPS forma

Mainshocks are aftershocks of conditional foreshocks: How do foreshock statistical properties emerge from aftershock laws

The inverse Omori law for foreshocks discovered in the 1970s states that the rate of earthquakes prior to a mainshock increases on average as a power law ~ 1/(t_c-t)^p' of the time to the mainshock occurring at t_c. Here, we show that this law results from the direct Omori law for aftershocks describing the power law decay ~ 1/(t-t_c)^p of seismicity after an earthquake, provided that any earthquake can trigger its suit of aftershocks. In this picture, the seismic activity at any time is the sum of the spontaneous tectonic loading and of the activity triggered by all preceding events weighted by their corresponding Omori law. The inverse Omori law then emerges as the expected (in a statistical sense) trajectory of seismicity, conditioned on the fact that it leads to the burst of seismic activity accompanying the mainshock. The often documented apparent decrease of the b-value of the GR law at the approach to the main shock results straightforwardly from the conditioning of the path of seismic activity culminating at the mainshock. In the space domain, we predict that the phenomenon of aftershock diffusion must have its mirror process reflected into an inward migration of foreshocks towards the mainshock. In this model, foreshock sequences are special aftershock sequences which are modified by the condition to end up in a burst of seismicity associated with the mainshock.Comment: Latex document of 35 pages, 10 figure

SCAMP:standardised, concentrated, additional macronutrients, parenteral nutrition in very preterm infants: a phase IV randomised, controlled exploratory study of macronutrient intake, growth and other aspects of neonatal care

<p>Abstract</p> <p>Background</p> <p>Infants born <29 weeks gestation are at high risk of neurocognitive disability. Early postnatal growth failure, particularly head growth, is an important and potentially reversible risk factor for impaired neurodevelopmental outcome. Inadequate nutrition is a major factor in this postnatal growth failure, optimal protein and calorie (macronutrient) intakes are rarely achieved, especially in the first week. Infants <29 weeks are dependent on parenteral nutrition for the bulk of their nutrient needs for the first 2-3 weeks of life to allow gut adaptation to milk digestion. The prescription, formulation and administration of neonatal parenteral nutrition is critical to achieving optimal protein and calorie intake but has received little scientific evaluation. Current neonatal parenteral nutrition regimens often rely on individualised prescription to manage the labile, unpredictable biochemical and metabolic control characteristic of the early neonatal period. Individualised prescription frequently fails to translate into optimal macronutrient delivery. We have previously shown that a standardised, concentrated neonatal parenteral nutrition regimen can optimise macronutrient intake.</p> <p>Methods</p> <p>We propose a single centre, randomised controlled exploratory trial of two standardised, concentrated neonatal parenteral nutrition regimens comparing a standard macronutrient content (maximum protein 2.8 g/kg/day; lipid 2.8 g/kg/day, dextrose 10%) with a higher macronutrient content (maximum protein 3.8 g/kg/day; lipid 3.8 g/kg/day, dextrose 12%) over the first 28 days of life. 150 infants 24-28 completed weeks gestation and birthweight <1200 g will be recruited. The primary outcome will be head growth velocity in the first 28 days of life. Secondary outcomes will include a) auxological data between birth and 36 weeks corrected gestational age b) actual macronutrient intake in first 28 days c) biomarkers of biochemical and metabolic tolerance d) infection biomarkers and other intravascular line complications e) incidence of major complications of prematurity including mortality f) neurodevelopmental outcome at 2 years corrected gestational age</p> <p>Trial registration</p> <p>Current controlled trials: <a href="http://www.controlled-trials.com/ISRCTN76597892">ISRCTN76597892</a>; EudraCT Number: 2008-008899-14</p