ProTx-I and ProTx-II: gating modifiers of voltage-gated sodium channels.

The tarantula venom peptides ProTx-I and ProTx-II inhibit voltage-gated sodium channels by shifting their voltage dependence of activation to a more positive potential, thus acting by a mechanism similar to that of potassium channel gating modifiers such as hanatoxin and VSTX1. ProTx-I and ProTx-II inhibit all sodium channel (Nav1) subtypes tested with similar potency and represent the first potent peptidyl inhibitors of TTX-resistant sodium channels. Like gating modifiers of potassium channels, ProTx-I and ProTx-II conform to the inhibitory cystine knot motif, and ProTx-II was demonstrated to bind to sodium channels in the closed state. Both toxins have been synthesized chemically, and ProTx-II, produced by recombinant means, has been used to map the interaction surface of the peptide with the Nav1.5 channel. In comparison, beta-scorpion toxins activate sodium channels by shifting the voltage dependence of activation to more negative potentials, and together these peptides represent valuable tools for exploring the gating mechanism of sodium channels.     

Gating modifier toxins of voltage-gated calcium channels.

Some of the most potent and specific inhibitors of voltage-gated calcium channels are peptide toxins that inhibit channel function not by occlusion of the channel pore, but rather by interfering with the voltage dependence and kinetics of channel opening and closing. Many such gating modifier toxins conform to the inhibitor cystine knot structural family and have primary sequence or functional mechanism similar to toxins that target voltage-gated sodium or potassium channels. This review introduces known gating modifiers of calcium channels, discusses the selectivity, binding sites, and mechanism of the toxin-channel interaction, and reviews the usefulness of these toxins as research tools and as the basis for novel calcium channel pharmacology and therapeutics.     

New evidence for a gating action of norepinephrine in central neuronal circuits of mammalian brain

Many previous studies have examined the effects of norepinephrine (NE) on neuronal responsiveness to synaptic inputs and putative transmitter substances and have described differential depressant actions of NE on stimulus evoked versus spontaneous discharge such that the "signal to noise" ratio of threshold responses was increased. In the present studies, similar experimental strategies employing a combination of microiontophoresis, single unit recording and afferent pathway stimulation in intact anesthetized and brain tissue slice preparations have revealed noradrenergic "gating" actions whereby weak or subthreshold synaptic stimuli can evoke threshold neuronal responses in the presence of iontophoretically applied NE or following electrical stimulation of the locus coeruleus. Overall, these results suggest that potentially threshold excitatory and inhibitory synaptic inputs may normally arrive at central neurons but appear weak or absent except during behavioral conditions favoring the synaptic release of NE. As such, these findings provide evidence that signal to noise ratio may not be the only potential modulatory action expressed by NE in noradrenergic target circuits of the mammalian brain.     

The estrous cycle and the olivo-cerebellar circuit

This study demonstrates that gating of responses of the rostral dorsal accessory olive (rDAO) to somatosensory stimulation varies across the estrous hormone cycle of the rat. The rDAO has been suggested as an error or event signal generator for the cerebellar cortex. Selective sensory gating of input to this structure may underlie this error signalling function. In the present study, as many as 23 single neurons were recorded simultaneously from either the forepaw or the snout areas of the rDAO. Responses of these neurons to electrical stimulation of peripheral afferents were determined during active movement or non-movement conditions. These results were then compared across the estrous cycle or after administration of the estrous hormones 17 -estradiol (E₂) and/or progesterone (P) to rats on diestrus or following E₂ priming. Elevations in circulating estrous hormones produced greater excitatory responses of rDAO neurons to stimulation during non-movement, and, conversely, enhanced inhibition of rDAO activity during active movement of the stimulated peripheral area compared with control diestrous conditions, suggesting that selective gating processes to the rDAO are enhanced by estrous hormones. The results of this study suggest that the night of behavioral estrus is associated with enhanced selective sensory gating processes associated with improved detection and processing of error signals.     

128层螺旋CT联合心电门控技术在支气管动脉成像中的应用

目的：探讨128层螺旋CT联合心电门控扫描技术在支气管动脉成像中的临床应用价值。方法：回顾性分析我院124例次胸部CT血管成像（CTA）数据,其中72例次行常规胸部CTA扫描数据列入对照组,52例次采用心电门控技术扫描数据列入观察组,对比分析观察两组支气管动脉的开口位置、走行、与相邻组织之间的解剖关系以及支气管动脉显示的清晰度。结果：对照组中33．33％（24／72）支气管动脉显示较清晰,58．33％（42／72）支气管动脉显示模糊,8．33％（6／72）没有发现支气管动脉;观察组52例次支气管动脉全部显示,其中86．54％（45／52）支气管动脉显示清晰,13．46％（7／52）支气管动脉显示模糊。结论：128层螺旋CT联合心电门控扫描技术与常规胸部血管成像相比,能更清晰地显示支气管动脉开口位置、形态、走行及其与相邻组织的关系,对支气管动脉源性疾病的治疗,特别是介入治疗术前评估有重要的临床应用价值。     

Gating of the HypoPP-1 mutations: I. Mutant-specific effects and cooperativity

Hypokalemic periodic paralysis type 1 (HypoPP-1) is a hereditary muscular disorder caused by point mutations in the gene encoding the voltage-gated Ca²⁺ channel α subunit (Ca_v1.1). Despite extensive research, the results on HypoPP-1 mutations are minor and controversial, as it is difficult to analyse Ca²⁺ channel activation macroscopically due to an existence of two open states. In this study, we heterologously expressed the wild-type and HypoPP-1 mutations introduced into the rabbit cardiac Ca²⁺ channel (R650H, R1362H, R1362G) in HEK-293 cells. To examine the cooperative effects of the mutations on channel gating, we expressed two double mutants (R650H/R1362H, R650H/R1362G). We performed whole-cell patch-clamp and, to obtain more information, applied a global fitting procedure whereby several current traces elicited by different potentials were simultaneously fit to the kinetic model containing four closed, two open and two inactivated states. We found that all HypoPP-1 mutations have “loss-of-function” features: D4/S4 mutations shift the equilibrium to the closed states, which results in reduced open probability, shorter openings and, therefore, in smaller currents, and the D2/S4 mutant slows the activation. In addition, HypoPP-1 histidine mutants favored the second open state O₂ with a possibly lower channel selectivity. Cooperativity between the D2/S4 and D4/S4 HypoPP-1 mutations manifested in dominant effects of the D4/S4 mutations on kinetics of the double mutants, suggesting different roles of D2/S4 and D4/S4 voltage sensors in the gating of voltage-gated calcium channels. Alexey Kuzmenkin and Chao Hang contributed equally to this work.     

Generalisability of sensory gating during passive movement of the legs

Movement-related gating of somatosensory evoked potentials in the upper limb is restricted mainly to nerve stimulation supplying the moved limb segment. In the lower limb, this principle may not be followed. Tibial nerve (stimulation at the knee) somatosensory evoked potentials (SEPs) and soleus H reflexes exhibit quite similar patterns of modulation during movement. We hypothesised that movement-related gating of initial SEPs in the leg would be generalised from ipsilateral to contralateral leg movement and that such sensory gating would not be generalised to modalities with no functional relevance to the movement. Somatosensory, visual, and auditory evoked potentials (SEPs, VEPs, and AEPs) were recorded from scalp electrodes during unilateral passive movement. Short-latency tibial nerve SEPs, representing the first cortical components, and soleus H reflexes in both the moved leg and the stationary leg were attenuated compared to non-movement controls (p<0.05). Neither VEPs nor middle latency AEPs were modulated (p>0.05). We conclude that sensory gating occurs during contralateral movement. This gating is absent in other sensory modalities with no apparent functional relationship to the imposed movement.     

The effects of intrafraction motion on dose homogeneity in a breast phantom with physical wedges, enhanced dynamic wedges, and ssIMRT

PURPOSE: This study attempts to compare how breathing motion affects intact-breast cancer patients between three different treatment techniques and to determine the degree of improvement on dose homogeneity when implementing gating therapy. METHODS AND MATERIALS: A breast phantom and respiratory simulator were designed to simulate respiratory motion to a first-order approximation. Film was used as a dosimeter, and static dosimetry data were used as a control for comparison. Three velocities of the breast phantom were studied, and gating therapy was introduced for each data set. Dose area histograms (DAHs) were calculated for a breast and a "lung" planning target area (PTA), and Normalized Agreement Test (NAT) indices were calculated in reference to the static case. RESULTS: Deviations from the static case were highest if the collimator speed was of the same magnitude as the speed of the target. In general, gating therapy improved dose uniformity to the breast PTA by up to 14% and reduced dose to the "lung" PTA by up to 24%. With step-and-shoot intensity-modulated radiation therapy (ssIMRT), gating the beam may compromise dose coverage of the breast PTA if the timing interval of the gate is too large. Gating the beam decreased NAT indices by 9 for physical wedges, by 16 for enhanced dynamic wedges, and by 6 for ssIMRT. CONCLUSIONS: Both the phantom and respiratory simulator are adequate for showing differences in dose distributions for all three treatment modalities. Gating therapy improves dose homogeneity to the PTAs and decreases the dose delivered to areas below the posterior border of the beams.     

核素心肌灌注显像与门控心室显像在缺血性心肌病中的对比

目的:对比研究核素心肌灌注显像与门控心室显像（GCBP）对缺血性心肌病诊断治疗的价值.方法:对79例缺血性心肌病进行核素心肌灌注显像与门控心室显像,计算各单项检查诊断的准确率和两项检查联合诊断的准确率,并进行对比分析.结果:两种显像方法单项诊断缺血性心肌病的准确率分别为78.5％、84.8％,联合诊断的准确性为93.7％,单项之间无显著差异（P>0.1）,单项与联合之间有显著差异（P<0.05）.结论:核素心肌灌注显像与门控心室显像联合评价对缺血性心肌病诊断治疗的价值优于单项检查.     

Inhibition of the activation pathway of the T-type calcium channel CaV3.1 by ProTxII

Toxins have been used extensively to probe the gating mechanisms of voltage-gated ion channels. Relatively few such tools are available to study the low-voltage activated T-type Ca channels, which underlie thalamic neuron firing and affect sleep, resistance to seizures, and weight gain. Here we show that ProTxII, a peptide toxin recently isolated from the venom of the tarantula spider Thrixopelma pruriens, dose-dependently inhibited Ca_V3.1 causing a decrease in current (81.6% ± 3.1% at −30 mV in 5 μM toxin) and a positive shift in the voltage range of activation (+34.5 mV ± 4.4 mV). Toxin-modified currents were slower to activate and faster to deactivate and they displayed a longer lag in the onset of current, i.e. the Cole-Moore shift, consistent with the inhibition of gating transitions along the activation pathway, particularly the final opening transition. Single-channel current amplitude and total gating charge were unaffected by toxin, ruling out a change in ion flux or channel dropout as mechanisms for the decrease in macroscopic conductance. A positive shift in the voltage range of gating charge movement (+30.6 mV ± 2.6 mV shift in the voltage of half maximal charge movement in the presence of 5 μM toxin) confirmed that ProTxII-induced gating perturbations in this channel occur at the level of the voltage sensors, and kinetic modeling based on these findings suggested that reductions in current magnitude could be largely accounted for by kinetic perturbations of activation.