Effect of knockout of α2δ-1 on action potentials in mouse sensory neurons

Gene deletion of the voltage-gated calcium channel auxiliary subunit α2δ-1 has been shown previously to have a cardiovascular phenotype, and a reduction in mechano- and cold sensitivity, coupled with delayed development of neuropathic allodynia. We have also previously shown that dorsal root ganglion (DRG) neuron calcium channel currents were significantly reduced in α2δ-1 knockout mice. To extend our findings in these sensory neurons, we have examined here the properties of action potentials (APs) in DRG neurons from α2δ-1 knockout mice in comparison to their wild-type (WT) littermates, in order to dissect how the calcium channels that are affected by α2δ-1 knockout are involved in setting the duration of individual APs and their firing frequency. Our main findings are that there is reduced Ca(2+) entry on single AP stimulation, particularly in the axon proximal segment, reduced AP duration and reduced firing frequency to a 400 ms stimulation in α2δ-1 knockout neurons, consistent with the expected role of voltage-gated calcium channels in these events. Furthermore, lower intracellular Ca(2+) buffering also resulted in reduced AP duration, and a lower frequency of AP firing in WT neurons, mimicking the effect of α2δ-1 knockout. By contrast, we did not obtain any consistent evidence for the involvement of Ca(2+)-activation of large conductance calcium-activated potassium (BK) and small conductance calcium-activated potassium (SK) channels in these events. In conclusion, the reduced Ca(2+) elevation as a result of single AP stimulation is likely to result from the reduced duration of the AP in α2δ-1 knockout sensory neurons.This article is part of the themed issue 'Evolution brings Ca(2+) and ATP together to control life and death'

Status of DIII-D plasma control

A key component of the DIII-D Advanced Tokamak and Radiative Divertor Programs is the development and implementation of methods to actively control a large number of plasma parameters. These parameters include plasma shape and position, total stored energy, density, rf loading resistance, radiated power and more detailed control of the current profile. To support this research goal, a flexible and easily expanded digital control system has been developed and implemented. We have made parallel progress in modeling of the plasma, poloidal coils, vacuum vessel, and power system dynamics and in ensuring the integrity of diagnostic and command circuits used in control. Recent activity has focused on exploiting the mature digital control platform through the implementation of simple feedback controls of more exotic plasma parameters such as enhanced divertor radiation, neutral pressure and Marfe creation and more sophisticated identification and digital feedback control algorithms for plasma shape, vertical position, and safety factor on axis (q{sub 0}). A summary of recent progress in each of these areas will be presented

A structured architecture for advanced plasma control experiments

Recent new and improved plasma control regimes have evolved from enhancements to the systems responsible for managing the plasma configuration on the DIII-D tokamak. The collection of hardware and software components designed for this purpose is known at DIII-D as the Plasma Control System or PCS. Several new user requirements have contributed to the rapid growth of the PCS. Experiments involving digital control of the plasma vertical position have resulted in the addition of new high performance processors to operate in real-time. Recent studies in plasma disruptions involving the use of neural network based software have resulted in an increase in the number of input diagnostic signals sampled. Better methods for estimating the plasma shape and position have brought about numerous software changes and the addition of several new code modules. Furthermore, requests for performing multivariable control and feedback on the current profile are continuing to add to the demands being placed on the PCS. To support all of these demands has required a structured yet flexible hardware and software architecture for maintaining existing capabilities and easily adding new ones. This architecture along with a general overview of the DIII-D Plasma Control System is described. In addition, the latest improvements to the PCS are presented

Fragile X mental retardation protein controls synaptic vesicle exocytosis by modulating N-type calcium channel density.

Fragile X syndrome (FXS), the most common heritable form of mental retardation, is characterized by synaptic dysfunction. Synaptic transmission depends critically on presynaptic calcium entry via voltage-gated calcium (CaV) channels. Here we show that the functional expression of neuronal N-type CaV channels (CaV2.2) is regulated by fragile X mental retardation protein (FMRP). We find that FMRP knockdown in dorsal root ganglion neurons increases CaV channel density in somata and in presynaptic terminals. We then show that FMRP controls CaV2.2 surface expression by targeting the channels to the proteasome for degradation. The interaction between FMRP and CaV2.2 occurs between the carboxy-terminal domain of FMRP and domains of CaV2.2 known to interact with the neurotransmitter release machinery. Finally, we show that FMRP controls synaptic exocytosis via CaV2.2 channels. Our data indicate that FMRP is a potent regulator of presynaptic activity, and its loss is likely to contribute to synaptic dysfunction in FXS

Computational Strategies in Optimizing a Real-Time Grad-Shafranov PDE Solver Using High-Level Graphical Programming and COTS Technology

Abstract This paper describes an alternative approach based on LabVIEW that solves the critical plasma shape and position control problems in tokamaks. Input signals from magnetic probes and flux loops are the constraints for a non-linear Grad-Shafranov PDE solver to calculate the magnetic equilibrium. An architecture based on offthe-shelf multi-core hardware and graphical software is described with an emphasis on seamless deployment from development system to real-time target. A number of mathematical challenges were addressed and several generally applicable numerical and mathematical strategies were developed to achieve the timing goals. Several benchmarks illustrate what can be achieved with such an approach. commercial-off-the-shelf (COTS) multi-core computers • In the first step, compute reduced iDST instead of full iDST. • In the second step, use optimized DST leveraging sparsity. Hardware and Software Grad-Shafranov PDE • Ψ is the poloidal flux function; • j is the current density; • R is the radial component; • Z is the axial component. • 33x65 grid Benchmarks Benchmarks for the real-time Grad-Shafranov solver and simultaneous function paramerisation and Grad-Shafranov solvers using 8 cores

Current status of DIII-D real-time digital plasma control

This paper describes the current status of real-time digital plasma control for the DIII-D tokamak. The digital plasma control system (PCS) has been in place at DIII-D since the early 1990s and continues to expand and improve in its capabilities to monitor and control plasma parameters for DIII-D fusion science experiments. The PCs monitors over 200 tokamak parameters from the DIII-D experiment using a real-time data acquisition system that acquires a new set of samples once every 60 {micro}s. This information is then used in a number of feedback control algorithms to compute and control a variety of parameters including those affecting plasma shape and position. A number of system related improvements has improved the usability and flexibility of the DIII-D PCS. These include more graphical user interfaces to assist in entering and viewing the large and ever growing number of parameters controlled by the PCS, increased interaction and accessibility from other DIII-D applications, and upgrades to the computer hardware and vended software. Future plans for the system include possible upgrades of the real-time computers, further links to other DIII-D diagnostic measurements such as real-time Thomson scattering analysis, and joint collaborations with other tokamak experiments including the NSTX at Princeton

A flexible software architecture for tokamak discharge control systems

The software structure of the plasma control system in use on the DIII-D tokamak experiment is described. This system implements control functions through software executing in real time on one or more digital computers. The software is organized into a hierarchy that allows new control functions needed to support the DIII-D experimental program to be added easily without affecting previously implemented functions. This also allows the software to be portable in order to create control systems for other applications. The tokamak operator uses an X-windows based interface to specify the time evolution of a tokamak discharge. The interface provides a high level view for the operator that reduces the need for detailed knowledge of the control system operation. There is provision for an asynchronous change to an alternate discharge time evolution in response to an event that is detected in real time. Quality control is enhanced through off-line testing that can make use of software- based tokamak simulators

Proteolytic maturation of α 2 δ represents a checkpoint for activation and neuronal trafficking of latent calcium channels

The auxiliary α2δ subunits of voltage-gated calcium channels are extracellular membrane-associated proteins, which are post-translationally cleaved into disulfide-linked polypeptides α2 and δ. We now show, using α2δ constructs containing artificial cleavage sites, that this processing is an essential step permitting voltage-dependent activation of plasma membrane N-type (CaV2.2) calcium channels. Indeed, uncleaved α2δ inhibits native calcium currents in mammalian neurons. By inducing acute cell-surface proteolytic cleavage of α2δ, voltage-dependent activation of channels is promoted, independent from the trafficking role of α2δ. Uncleaved α2δ does not support trafficking of CaV2.2 channel complexes into neuronal processes, and inhibits Ca2+ entry into synaptic boutons, and we can reverse this by controlled intracellular proteolytic cleavage. We propose a model whereby uncleaved α2δ subunits maintain immature calcium channels in an inhibited state. Proteolytic processing of α2δ then permits voltage-dependent activation of the channels, acting as a checkpoint allowing trafficking only of mature calcium channel complexes into neuronal processes