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The gabapentenoids such as gabapentin (GP) and pregabalin are approved for the treatment of chronic pain, but their utility is limited by persistent side effects. These adverse effects result from GPs affecting many types of neurons and muscle cells, not just the pain-sensing neurons that are the intended targets. We have recently discovered a type of peripheral neuron, rat sympathetic neurons from the superior cervical ganglion (SCG), that is uniquely insensitive to GP effects. Currents were measured using whole-cell patch-clamp electrophysiology from cells in primary culture from either the SCG or the Nodose Ganglion (NDG) as a positive control for the effects of GP. We find that the calcium current density was dramatically reduced by GP pretreatment in NDG neurons, but that neurons from the SCG were resistant. Further, when GP was cytoplasmically injected into these neurons, the resistance of SCG neurons to GP treatment persisted. These data demonstrate that rat sympathetic neurons appear to be uniquely resistant to GP treatment. These results may help us to better understand the mechanism of action of, and resistance to, GP in altering calcium channel current density, which may help to develop future treatments with fewer side effects. [ABSTRACT FROM AUTHOR]

In this work, a novel trench-gated CAVET featuring a p-GaN island for breakdown voltage improvement is proposed. The p-GaN island inserted between the two p-GaN current-blocking-layer (CBL) constructs a dual-current-aperture vertical transistor (DCAVET), which enables to engineer the electric-field (E-field) distribution in the buried p–n-junction for voltage sustaining. The device operation mechanism and characteristics were investigated by TCAD simulation. By delicately designing the device structural parameters and optimizing the doping concentration, the premature punchthrough and high ${E}$ -field induced avalanche breakdown were effectively suppressed at even higher reverse blocking voltage. The proposed DCAVET achieves excellent balance between punchthrough and avalanche breakdown, delivering a high breakdown voltage of 1504 V and low ${R}_{\text {on,sp}}$ of 0.77 $\text{m}\Omega \cdot $ cm2. The trench gate DCAVET demonstrates a flexible approach to engineer the ${E}$ -field distribution to achieve kilo-volts GaN power transistors. [ABSTRACT FROM AUTHOR]

Cav1.4 L-type Ca2+ channels are predominantly expressed in retinal neurons, particularly at the photoreceptor terminals where they mediate sustained Ca2+ entry needed for continuous neurotransmitter release at their ribbon synapses. Cav1.4 channel gating properties are controlled by accessory subunits, associated regulatory proteins, and also alternative splicing. In humans, mutations in the CACNA1F gene encoding for Cav1.4 channels are associated with X-linked retinal disorders such as congenital stationary night blindness type 2. Mutations in the Cav1.4 protein result in a spectrum of altered functional channel activity. Several mouse models broadened our understanding of the role of Cav1.4 channels not only as Ca2+ source at retinal synapses but also as synaptic organizers. In this review, we highlight different structural and functional phenotypes of Cav1.4 mutations that might also occur in patients with congenital stationary night blindness type 2. A further important yet mostly neglected aspect that we discuss is the influence of alternative splicing on channel dysfunction. We conclude that currently available functional phenotyping strategies should be refined and summarize potential specific therapeutic options for patients carrying Cav1.4 mutations. Importantly, the development of new therapeutic approaches will permit a deeper understanding of not only the disease pathophysiology but also the physiological function of Cav1.4 channels in the retina. [ABSTRACT FROM AUTHOR]

In this treatise, we introduce a novel polarization modulation (PM) scheme, where we capitalize on the reconfigurable polarization antenna design for exploring the polarization domain degrees of freedom, thus boosting the system throughput. More specifically, we invoke the inherent properties of a dual polarized (DP) antenna for transmitting additional information carried by the axial ratio (AR) and tilt angle of elliptic polarization, in addition to the information streams transmitted over its vertical (V) and horizontal (H) components. Furthermore, we propose a special algorithm for generating an improved PM constellation tailored especially for wireless PM modulation. We also provide an analytical framework to compute the average bit error rate (ABER) of the PM system. Furthermore, we characterize both the discrete-input continuous-output memoryless channel (DCMC) capacity and the continuous-input continuous-output memoryless channel (CCMC) capacity as well as the upper and lower bounds of the CCMC capacity. The results show the superiority of our proposed PM system over conventional modulation schemes in terms of both higher throughput and lower BER. In particular, our simulation results indicate that the gain achieved by the proposed $Q$ -dimensional PM scheme spans between 10dB and 20dB compared to the conventional modulation. It is also demonstrated that the PM system attains between 54% and 87.5% improvements in terms of ergodic capacity. Furthermore, we show that this technique can be applied to MIMO systems in a synergistic manner in order to achieve the target data rate target for 5G wireless systems with much less system resources (in terms of bandwidth and the number of antennas) compared to existing MIMO techniques. [ABSTRACT FROM AUTHOR]

In this paper, a study of the channel modulation instability of commercial p-GaN gate HEMTs is presented. During the gate-voltage stress test, substantial R DS(ON) variations up to 78 mΩ (93.8%) were observed. It is found that the p-GaN/AlGaN/GaN gate structure enables the injection of holes and electrons, which can be captured by the donor/acceptor-like traps located in the AlGaN layer. Therefore, the trapped holes and electrons concurrently modulate the channel conductivity, resulting in R DS(ON) variations. Device simulation was performed to help explain the mechanism from the perspective of energy band. In addition, results reveal that with the recommended working gate-voltage stress V GS = 7 V, the on-state resistance, the threshold voltage and the off-state drain to source leakage current vary up to 8 mΩ (16.3%), 0.2 V (14.8%) and 12.8 μA (42.66%) within 1 h, respectively, which could raise reliability issues for the power electronics applications of p-GaN gate HEMTs. [ABSTRACT FROM AUTHOR]

Abstract: The device characteristics of Ti–InSnO thin film transistors (TFTs) with modulated channels were investigated. The field effect mobility was enhanced to 14.9 cm2/Vs in the channel-modulated TFT. The electrical performance of the TFT device was improved by the insertion of a high carrier concentration layer at the channel/gate insulator and channel/electrode interfaces. It was due to the enhancement of carrier accumulation and the reduction of parasitic resistance via channel modulation. The threshold voltage was controlled at moderate value. These results indicate that the device characteristic of TFTs can be enhanced by the modulated channel structure. [Copyright &y& Elsevier]

Abstract: Calmodulin (CaM) is an important regulator of Kv7.x (KCNQx) voltage-gated potassium channels. Channels from this family produce neuronal M currents and cardiac and auditory IKS currents and harbor mutations that cause arrhythmias, epilepsy, and deafness. Despite extensive functional characterization, biochemical and structural details of the interaction between CaM and the channel have remained elusive. Here, we show that both apo-CaM and Ca2+/CaM bind to the C-terminal tail of the neuronal channel Kv7.4 (KCNQ4), which is involved in both hearing and mechanosensation. Interactions between apo-CaM and the Kv7.4 tail involve two C-terminal tail segments, known as the A and B segments, whereas the interaction between Ca2+/CaM and the Kv7.4 C-terminal tail requires only the B segment. Biochemical studies show that the calcium dependence of the CaM:B segment interaction is conserved in all Kv7 subtypes. X-ray crystallographic determination of the structure of the Ca2+/CaM:Kv7.4 B segment complex shows that Ca2+/CaM wraps around the Kv7.4 B segment, which forms an α-helix, in an antiparallel orientation that embodies a variation of the classic 1-14 Ca2+/CaM interaction motif. Taken together with the context of prior studies, our data suggest a model for modulation of neuronal Kv7 channels involving a calcium-dependent conformational switch from an apo-CaM form that bridges the A and B segments to a Ca2+/CaM form bound to the B-helix. The structure presented here also provides a context for a number of disease-causing mutations and for further dissection of the mechanisms by which CaM controls Kv7 function. [Copyright &y& Elsevier]

The sensory neuron-specific sodium channel Nav1.8 and p38 mitogen-activated protein kinase are potential therapeutic targets within nociceptive dorsal root ganglion (DRG) neurons in inflammatory, and possibly neuropathic, pain. Nav1.8 channels within nociceptive DRG neurons contribute most of the inward current underlying the depolarizing phase of action potentials. Nerve injury and inflammation of peripheral tissues cause p38 activation in DRG neurons, a process that may contribute to nociceptive neuron hyperexcitability, which is associated with pain. However, how substrates of activated p38 contribute to DRG neuron hyperexcitability is currently not well understood. We report here, for the first time, that Nav1.8 and p38 are colocalized in DRG neurons, that Nav1.8 within DRG neurons is a substrate for p38, and that direct phosphorylation of the Nav1.8 channel by p38 regulates its function in these neurons. We show that direct phosphorylation of Nav1.8 at two p38 phospho-acceptor serine residues on the L1 loop (S551 and S556) causes an increase in Nav1.8 current density that is not accompanied by changes in gating properties of the channel. Our study suggests a mechanism by which activated p38 contributes to inflammatory, and possibly neuropathic, pain through a p38-mediated increase of Nav1.8 current density. [ABSTRACT FROM AUTHOR]

Abstract: The actions of the ciliary neurotrophic factor (CNTF) were assessed on adult mouse skeletal muscle L-type Ca2+ currents and on Ca2+ release from sarcoplasmic reticulum. Currents were measured with the whole cell patch clamp technique. Ca2+ signals in response to single action potentials were recorded with Fluo3-AM. CNTF (20ng/ml) reversibly reduced the amplitude of Ca2+ channel currents by 50% within 15min. In addition, CNTF greatly increased the rate of inactivation during depolarizing pulses and shifted the steady state inactivation curve by −12mV. The effects of CNTF were mimicked by the PKC activator PMA and prevented by the PKC-inhibitor chelerythrine. In contrast to the effects on the Ca2+ conductance, charge movement and Ca2+ signals remained unaffected by CNTF. These results suggest that CNTF can rapidly decrease muscle Ca2+ channel currents by promoting inactivation, probably through an intracellular PKC-dependent mechanism. [Copyright &y& Elsevier]

The focus of the present study is the molecular and functional characterization of four splice variants of the human Nav1.3 α subunit. These subtypes arise due to the use of alternative splice donor sites of exon 12, which encodes a region of the α subunit that resides in the intracellular loop between domains I and II. This region contains several important phosphorylation sites that modulate Na+ channel kinetics in related sodium channels, i.e. Nav1.2. While three of the four Nav1.3 isoforms, 12v1, 12v3 and 12v4 have been previously identified in human, 12v2 has only been reported in rat. Herein, we evaluate the distribution of these splice variants in human tissues and the functional characterization of each of these subtypes. We demonstrate by reverse transcriptase-polymerase chain reaction (RT-PCR) that each subtype is expressed in the spinal cord, thalamus, amygdala, cerebellum, adult and fetal whole brain and heart. To investigate the functional properties of these different splice variants, each α subunit isoform was cloned by RT-PCR from human fetal brain and expressed in Xenopus oocytes. Each isoform exhibited functional voltage-dependent Na+ channels with similar sensitivities to tetrodotoxin (TTX) and comparable current amplitudes. Subtle shifts in the V1/2 of activation and inactivation (2–3 mV) were observed among the four isoforms, although the functional significance of these differences remains unclear. This study has demonstrated that all four human splice variants of the Nav1.3 channel α subunit are widely expressed and generate functional TTX-sensitive Na+ channels that likely modulate cellular excitability. [ABSTRACT FROM AUTHOR]

The Drosophila Slowpoke calcium-dependent potassium channel (dSlo) binding protein Slob was discovered by a yeast two-hybrid screen using the carboxy-terminal tail region of dSlo as bait. Slob binds to and modulates the dSlo channel. We have found that there are several Slob proteins, resulting from multiple translational start sites and alternative splicing, and have named them based on their molecular weights (in kD). The larger variants, which are initiated at the first translational start site and are called Slob71 and Slob65, shift the voltage dependence of dSlo activation, measured by the whole cell conductance-voltage relationship, to the left (less depolarized voltages). Slob53 and Slob47, initiated at the third translational start site, also shift the dSlo voltage dependence to the left. In contrast, Slob57 and Slob51, initiated at the second translational start site, shift the conductance-voltage relationship of dSlo substantially to more depolarized voltages, cause an apparent dSlo channel inactivation, and increase the deactivation rate of the channel. These results indicate that the amino-terminal region of Slob plays a critical role in its modulation of dSlo. [ABSTRACT FROM AUTHOR]

In skeletal muscle, the waveform of Ca2+ release under clamp depolarization exhibits an early peak. Its decay reflects an inactivation, which locally corresponds to the termination of Ca2+ sparks, and is crucial for rapid control. In cardiac muscle, both the frequency of spontaneous sparks (i.e., their activation) and their termination appear to be strongly dependent on the Ca2+ content in the sarcoplasmic reticulum (SR). In skeletal muscle, no such role is established. Seeking a robust measurement of Ca2+ release and a way to reliably modify the SR content, we combined in the same cells the "EGTA/phenol red" method (Pape et al, 1995) to evaluate Ca2+ release, with the "removal" method (Melzer et al., 1987) to evaluate release flux. The cytosol of voltage-clamped frog fibers was equilibrated with EGTA (36 mM), antipyrylazo III, and phenol red, and absorbance changes were monitored simultaneously at three wavelengths, affording largely independent evaluations of Δ[H+] and Δ[Ca2+] from which the amount of released Ca2+ and the release flux were independently derived. Both methods yielded mutually consistent evaluations of flux. While the removal method gave a better kinetic picture of the release waveform, EGTA/phenol red provided continuous reproducible measures of calcium in the SR (CaSR). Steady release permeability (P), reached at the end of a 120-ms pulse, increased as CaSR was progressively reduced by a prior conditioning pulse, reaching 2.34-fold at 25% of resting CaSR (four cells). Peak P, reached early during a pulse, increased proportionally much less with SR depletion, decreasing at very low CaSR. The increase in steady P upon depletion was associated with a slowing of the rate of decay of P after the peak (i.e., a slower inactivation of Ca2+ release). These results are consistent with a major inhibitory effect of cytosolic (rather than intra-SR) Ca2+ on the activity of Ca2+ release channels. [ABSTRACT FROM AUTHOR]

The slowpoke channel binding protein Slob from Drosophila melanogaster contains a putative protein kinase domain within its amino acid sequence. We find that Slob exhibits weak and barely detectable protein kinase activity in vitro, as evidenced by autophosphorylation and by phosphorylation of exogenously added histone as substrate. The phosphorylation of histone is enhanced markedly when Slob is pretreated with the catalytic subunit of cyclic AMP-dependent protein kinase (PKAc). Mass spectrometric and mutational analysis demonstrates that the major site of phosphorylation by PKAc within Slob is serine 54. The enhancement of Slob kinase activity by PKAc pretreatment is eliminated when serine 54 in Slob is mutated to alanine (S54A). Furthermore, Slob kinase activity is enhanced in an S54E mutant that mimics phosphorylation at serine 54, and there is no further enhancement of S54E Slob kinase activity by pretreatment with PKAc. The results are consistent with the hypothesis that Slob exhibits regulatable protein kinase activity, whose activity is enhanced by phosphorylation at serine 54. [Copyright &y& Elsevier]

To determine the interaction site(s) of ATP-sensitive K+ (KATP) channels for G-proteins, sulfonylurea receptor (SUR2A or SUR1) and pore-forming (Kir6.2) subunits were reconstituted in the mammalian cell line, COS-7. Intracellular application of the G-protein βγ2-subunits (Gβγ2) caused a reduction of ATP-induced inhibition of Kir6.2/SUR channel activities by lessening the ATP sensitivity of the channels. Gβγ2 bound in vitro to both intracellular (loop-NBD) and C-terminal segments of SUR2A, each containing a nucleotide-binding domain (NBD). Furthermore, a single amino acid substitution in the loop-NBD of SUR (Arg656Ala in SUR2A or Arg665Ala in SUR1) abolished the Gβγ2-dependent alteration of the channel activities. These findings provide evidence that Gβγ modulates KATP channels through a direct interaction with the loop-NBD of SUR. [ABSTRACT FROM AUTHOR]

Background: The GABAA system is believed to be one of the crucial target sites for ethanol. However, in the literature, data using various preparations yielded controversial conclusions regarding the ethanol potency to modulate the activity of GABAA receptors. We have previously shown that the potency of n-alcohols to potentiate GABA-induced currents is correlated with their carbon chain length. This correlation was further compared among four cell types in an attempt to explain the variable potencies of ethanol to potentiate GABA responses. Methods: Whole-cell patch clamp experiments were performed to determine and compare the potencies of n-alcohols in potentiating GABA-induced currents in rat dorsal root ganglion (DRG) neurons, human embryonic kidney cells expressing the rat α1β2γ2S or α1β2γ2L subunits, and rat cortical neurons. Results: The GABAA, receptors of the four cell types tested were all sensitive to n-alcohols, albeit with different potencies and efficacies. The effective concentration to increase GABA-induced currents to 125% of control (EC125) was correlated with the carbon chain length of n-alcohols, but slopes for this relationship are different among DRG neurons, the α1β2γ2S, and α1β2γ2L subunits. Thus, the potencies of lower alcohols such as ethanol differed among these cell types although higher alcohols such as n-octanol were almost equally potent. In cortical neurons, however, the relationship was shifted in the direction of longer carbon chains, indicating that their sensitivity was lower than those of the other three cell types. The ethanol EC125 values as obtained by experiments or those by extrapolation (in parenthesis) from the EC125-carbon chain length relationship were: 169 (103) mM for DRG neurons, 501 (333) mM for the α1β2γ2L subunits, 781 (674) mM for the α1β2γ2S subunits, and (1897) mM for cortical neurons. Conclusions: It was concluded that the GABA A receptors of these four cell types were basically sensitive to n-alcohols including ethanol but the sensitivity curve was shifted to the lower side in the order of decreasing sensitivity of DRG neurons > α1β2γ2L > α1β2γ2S > cortical neurons. [ABSTRACT FROM AUTHOR]

Energy‐efficiency (EE) in antenna selection multi‐input–multi‐output (MIMO) systems over Nakagami‐m fading channels is investigated. An EE metric is defined as the number of successfully received bits per unit of energy consumption, which takes into account several important system parameters such as channel coding and modulation. An optimisation problem that maximises the EE metric subject to an error‐performance constraint is formulated. On the basis of an analysis of this problem, the optimal value of the average energy per transmitted data symbol is obtained, such that the EE in the system is maximised. Simulation results are provided to validate the analysis. [ABSTRACT FROM AUTHOR]

A new approach of reliable image and video transmission over noisy channels is proposed. For subband decomposed image and video, combined source coding and channel modulation design can achieve high compression efficiency and preferable quality. Further performance gain is obtained by multiresolution modulation as well as a bit remapping scheme that assigns efficient mapping from each source codeword to channel modulation points. We show that the combined source coding and modulation design outperforms conventional approaches, which design source coding and modulation separately. A simple channel distortion approximation is derived by applying a bit-remapping scheme, which allows the power allocation to be employed to further enhance the performance. Compared to the joint source and channel coding with a binary phase shift keying modulation system and fixed modulation with the one-to-one intelligent mapping system, the proposed system performs better in a middle-range signal-to-noise ratio and low channel bandwidth. The simulation is carried out on additive white Gaussian noise channels [ABSTRACT FROM PUBLISHER]

To develop a malleable system to model the well-described, physiological interactions between Gq/11-coupled receptor and Gi/o-coupled receptor signaling, we coexpressed the endothelin A receptor, the μ-opioid receptor, and the G protein-coupled inwardly rectifying potassium channel (Kir 3) heteromultimers in Xenopus laevis oocytes. Activation of the Gi/o-coupled μ-opioid receptor strongly increased Kir 3 channel current, whereas activation of the Gq/11-coupled endothelin A receptor inhibited the Kir 3 response evoked by μ-opioid receptor activation. The magnitude of the inhibition of Kir 3 was channel subtype specific; heteromultimers composed of Kir 3.1 and Kir 3.2 or Kir 3.1 and Kir 3.4 were significantly more sensitive to the effects of endothelin-1 than heteromultimers composed of Kir 3.1 and Kir 3.5. The difference in sensitivity of the heteromultimers suggests that the endothelin-induced inhibition of the opioid-activated current was caused by an effect at the channel rather than at the apioid receptor. The endothelin-1-mediated inhibition was mimicked by arachidonic acid and blocked by the phospholipase A2 inhibitor arachidonoyl trifluoromethyl ketone. Consistent with a possible phospholipase A2-mediated mechanism, the endothelin-1 effect was blocked by calcium chelation with BAPTA-AM and was not affected by kinase inhibition by either staurosporine or genistein. The data suggest the hypothesis that Gq/11-coupled receptor activation may interfere with Gi/o-coupled receptor signaling by the activation of phospholipase A2 and subsequent inhibition of effector function by a direct effect of an eicosanoid on the channel. [ABSTRACT FROM AUTHOR]

In recent years, it has become evident that cholesterol plays a direct role in the modulation of a variety of ion channels. In most cases, cholesterol downregulates channel activity. In contrast, our earlier studies have demonstrated that atrial G protein inwardly rectifying potassium (GIRK) channels are upregulated by cholesterol. Recently, we have shown that hippocampal GIRK currents are also upregulated by cholesterol. A combined computational-experimental approach pointed to putative cholesterol-binding sites in the transmembrane domain of the GIRK2 channel, the primary subunit in hippocampal GIRK channels. In particular, the principal cholesterol-binding site was located in the center of the transmembrane domain in between the inner and outer α-helices of 2 adjacent subunits. Further studies pointed to a similar cholesterol-binding site in GIRK4, a major subunit in atrial GIRK channels. However, a close look at a sequence alignment of the transmembrane helices of the 2 channels reveals surprising differences among the residues that interact with the cholesterol molecule in these 2 channels. Here, we compare the residues that form putative cholesterol-binding sites in GIRK2 and GIRK4 and discuss the similarities and differences among them. [ABSTRACT FROM AUTHOR]