Sodium channel slow inactivation interferes with open channel block

Mutations in the voltage-gated sodium channel Nav1.7 are linked to inherited pain syndromes such as erythromelalgia (IEM) and paroxysmal extreme pain disorder (PEPD). PEPD mutations impair Nav1.7 fast inactivation and increase persistent currents. PEPD mutations also increase resurgent currents, which involve the voltage-dependent release of an open channel blocker. In contrast, IEM mutations, whenever tested, leave resurgent currents unchanged. Accordingly, the IEM deletion mutation L955 (ΔL955) fails to produce resurgent currents despite enhanced persistent currents, which have hitherto been considered a prerequisite for resurgent currents. Additionally, ΔL955 exhibits a prominent enhancement of slow inactivation (SI). We introduced mutations into Nav1.7 and Nav1.6 that either enhance or impair SI in order to investigate their effects on resurgent currents. Our results show that enhanced SI is accompanied by impaired resurgent currents, which suggests that SI may interfere with open-channel block

A SCN9A gene-encoded dorsal root ganglia sodium channel polymorphism associated with severe fibromyalgia

<p>Abstract</p> <p>Background</p> <p>A consistent line of investigation suggests that autonomic nervous system dysfunction may explain the multi-system features of fibromyalgia (FM); and that FM is a sympathetically maintained neuropathic pain syndrome. Dorsal root ganglia (DRG) are key sympathetic-nociceptive short-circuit sites. Sodium channels located in DRG (particularly Nav1.7) act as molecular gatekeepers for pain detection. Nav1.7 is encoded in gene SCN9A of chromosome 2q24.3 and is predominantly expressed in the DRG pain-sensing neurons and sympathetic ganglia neurons. Several SCN9A sodium channelopathies have been recognized as the cause of rare painful dysautonomic syndromes such as paroxysmal extreme pain disorder and primary erythromelalgia. The aim of this study was to search for an association between fibromyalgia and several SCN9A sodium channels gene polymorphisms.</p> <p>Methods</p> <p>We studied 73 Mexican women suffering from FM and 48 age-matched women who considered themselves healthy. All participants filled out the Fibromyalgia Impact Questionnaire (FIQ). Genomic DNA from whole blood containing EDTA was extracted by standard techniques. The following SCN9A single-nucleotide polymorphisms (SNP) were determined by 5' exonuclease TaqMan assays: rs4371369; rs4387806; rs4453709; rs4597545; rs6746030; rs6754031; rs7607967; rs12620053; rs12994338; and rs13017637.</p> <p>Results</p> <p>The frequency of the rs6754031 polymorphism was significantly different in both groups (<it>P </it>= 0.036) mostly due to an absence of the GG genotype in controls. Interestingly; patients with this rs6754031 GG genotype had higher FIQ scores (median = 80; percentile 25/75 = 69/88) than patients with the GT genotype (median = 63; percentile 25/75 = 58/73; <it>P </it>= 0.002) and the TT genotype (median = 71; percentile 25/75 = 64/77; <it>P </it>= 0.001).</p> <p>Conclusion</p> <p>In this ethnic group; a disabling form of FM is associated to a particular SCN9A sodium channel gene variant. These preliminary results raise the possibility that some patients with severe FM may have a dorsal root ganglia sodium channelopathy.</p

Bone mineral density of the femoral neck in resurfacing hip arthroplasty: Precision of DXA biased by region of interest and rotation of the hip

Resurfacing total hip arthroplasty (RTHA) may preserve the femoral neck bone stock postoperatively. Bone mineral density (BMD) may be affected by the hip position, which might bias longitudinal studies. We investigated the dependency of BMD precision on type of ROI and hip position

Painful and painless mutations of SCN9A and SCN11A voltage-gated sodium channels

Chronic pain is a global problem affecting up to 20% of the world’s population and has a significant economic, social and personal cost to society. Sensory neurons of the dorsal root ganglia (DRG) detect noxious stimuli and transmit this sensory information to regions of the central nervous system (CNS) where activity is perceived as pain. DRG neurons express multiple voltage-gated sodium channels that underlie their excitability. Research over the last 20 years has provided valuable insights into the critical roles that two channels, NaV1.7 and NaV1.9, play in pain signalling in man. Gain of function mutations in NaV1.7 cause painful conditions while loss of function mutations cause complete insensitivity to pain. Only gain of function mutations have been reported for NaV1.9. However, while most NaV1.9 mutations lead to painful conditions, a few are reported to cause insensitivity to pain. The critical roles these channels play in pain along with their low expression in the CNS and heart muscle suggest they are valid targets for novel analgesic drugs

High-fidelity quantum logic gates using trapped-ion hyperfine qubits

We demonstrate laser-driven two-qubit and single-qubit logic gates with fidelities 99.9(1)% and 99.9934(3)% respectively, significantly above the ≈ 99% minimum threshold level required for faulttolerant quantum computation, using qubits stored in hyperfine ground states of calcium-43 ions held in a room-temperature trap. We study the speed/fidelity trade-off for the two-qubit gate, for gate times between 3.8 μs and 520 μs, and develop a theoretical error model which is consistent with the data and which allows us to identify the principal technical sources of infidelity

Precision measurement of the 43Ca+ nuclear magnetic moment

We report precision measurements of the nuclear magnetic moment of 43Ca+, made by microwave spectroscopy of the 4s2S1/2∣∣F=4,M=0⟩→∣∣F=3,M=1⟩ ground level hyperfine clock transition at a magnetic field of ≈146G, using a single laser-cooled ion in a Paul trap. We measure a clock-transition frequency of f=3199941076.920(46)Hz from which we determine μI/μN=−1.315350(9)(1) where the uncertainty (9) arises from uncertainty in the hyperfine A constant, and the (1) arises from the uncertainty in our measurement. This measurement is not corrected for diamagnetic shielding due to the bound electrons. We make a second measurement which is less precise but agrees with the first. We use our μI value in combination with previous NMR results to extract the change in shielding constant of calcium ions due to solvation in D2O:Δσ=−0.00022(1)

High-fidelity trapped-ion quantum logic using near-field microwaves

We demonstrate a two-qubit logic gate driven by near-field microwaves in a room-temperature microfabricated surface ion trap. We introduce a dynamically decoupled gate method, which stabilizes the qubits against fluctuating energy shifts and avoids the need to null the microwave field. We use the gate to produce a Bell state with fidelity 99.7(1)%, after accounting for state preparation and measurement errors. The gate is applied directly to ^{43}Ca^{+} hyperfine "atomic clock" qubits (coherence time T_{2}^{*}≈50  s) using the oscillating magnetic field gradient produced by an integrated microwave electrode

High-fidelity trapped-ion quantum logic using near-field microwaves

We demonstrate a two-qubit logic gate driven by near-field microwaves in a room-temperature microfabricated surface ion trap. We introduce a dynamically decoupled gate method, which stabilizes the qubits against fluctuating energy shifts and avoids the need to null the microwave field. We use the gate to produce a Bell state with fidelity 99.7(1)%, after accounting for state preparation and measurement errors. The gate is applied directly to ^{43}Ca^{+} hyperfine "atomic clock" qubits (coherence time T_{2}^{*}≈50  s) using the oscillating magnetic field gradient produced by an integrated microwave electrode