Reduction of the Diffusion Equations of Ion Channel Clusters with Virtually No Increase in the Error Bound

A stochastic differential formulation for the collective dynamics of ion channel clusters in excitable membranes is developed from the so-called “reduced strong diffusion formulation”. In this error bound optimizing reduced formulation, the potassium channel states [Formula: see text] and [Formula: see text], and, the sodium channel states [Formula: see text] and [Formula: see text] are the retained states; consequently, the formulation accommodates only four channel variables and five white noises. The accuracy of the formulation is tested over the standard deviations and autocorrelation times of the channel density fluctuations. The findings are seen to be virtually identical to the corresponding results from the exact microscopic Markov simulations. The formulation arises as the most accurate model with that structural simplicity, thus making it an important model for both analytic analyses and numerical simulations in the study of finite-sized membranes.

The Pivotal Potentials of Scorpion Buthus Martensii Karsch-Analgesic-Antitumor Peptide in Pain Management and Cancer

Scorpion Buthus martensii Karsch -analgesic-antitumor peptide (BmK AGAP) has been used to treat diseases like tetanus, tuberculosis, apoplexy, epilepsy, spasm, migraine headaches, rheumatic pain, and cancer in China. AGAP is a distinctive long-chain scorpion toxin with a molecular mass of 7142 Da and composed of 66 amino acids cross-linked by four disulfide bridges. Voltage-gated sodium channels (VGSCs) are present in excitable membranes and partakes in essential roles in action potentials generation as compared to the significant function of voltage-gated calcium channels (VGCCs). A total of nine genes (Nav1.1–Nav1.9) have been recognized to encode practical sodium channel isoforms. Nav1.3, Nav1.7, Nav1.8, and Nav1.9 have been recognized as potential targets for analgesics. Nav1.8 and Nav1.9 are associated with nociception initiated by inflammation signals in the neuronal pain pathway, while Nav1.8 is fundamental for neuropathic pain at low temperatures. AGAP has a sturdy inhibitory influence on both viscera and soma pain. AGAP potentiates the effects of MAPK inhibitors on neuropathic as well as inflammation-associated pain. AGAP downregulates the secretion of phosphorylated p38, phosphorylated JNK, and phosphorylated ERK 1/2 in vitro. AGAP has an analgesic activity which may be an effective therapeutic agent for pain management because of its downregulation of PTX3 via NF-κB and Wnt/beta-catenin signaling pathway. In cancers like colon cancer, breast cancer, lymphoma, and glioma, rAGAP was capable of blocking the proliferation. Thus, AGAP is a promising therapy for these tumors. Nevertheless, research is needed with other tumors.

Cooperativity and Steep Voltage Dependence in a Bacterial Channel

This paper reports on the discovery of a novel three-membrane channel unit exhibiting very steep voltage dependence and strong cooperative behavior. It was reconstituted into planar phospholipid membranes formed by the monolayer method and studied under voltage-clamp conditions. The behavior of the novel channel-former, isolated from Escherichia coli, is consistent with a linearly organized three-channel unit displaying steep voltage-gating (a minimum of 14 charges in the voltage sensor) that rivals that of channels in mammalian excitable membranes. The channels also display strong cooperativity in that closure of the first channel permits the second to close and closure of the second channel permits closure of the third. All three have virtually the same conductance and selectivity, and yet the first and third close at positive potentials whereas the second closes at negative potentials. Thus, is it likely that the second channel-former is oriented in the membrane in a direction opposite to that of the other two. This novel structure is named “triplin.” The extraordinary behavior of triplin indicates that it must have important and as yet undefined physiological roles.

Serum ionic dysequilibria in clinical opioid dependence: Cross-sectional and longitudinal studies

Introduction: Despite an increasing awareness that the activity of excitable membranes is determined by the underlying ionic gradients across them, and their importance in drug dependency, we were not able to identify any reports of comparing the electrolyte composition of opioid-dependent and non-addicted controls. Methods: Linear regression was used to compare clinical pathology blood results taken from 2699 opioid-dependent patients (ODP) and 5307 medical control (MC) patients on a total of 21,734 occasions for the period 1995–2015. The presence of a hepatitis C antibody test was used to separate OPD and MC patients. Results: The mean age among ODP and MC was 33.51 ± 0.16 and 37.99 ± 0.23 years, respectively ( p < 0.0001). The groups were 71.5% and 54.2% male ( p < 0.0001). Drug use in this cohort has been reported previously. Analysis of sodium, haemoglobin and albumin were used to exclude marked effects of haemodilution/haemoconcentration. Repeated measures linear regression against age and time showed depressed levels of bicarbonate ( p < 0.0001) and potassium ( p < 0.05) and elevated levels of chloride ( p < 0.025) and anions ( p < 0.01) in ODP in both sexes. Multiple regression in mixed-effects models showed that these effects were all worse in females ( p = 0.0001). Conclusion: This data shows that opioid dependence is associated with significant changes in chloride, potassium, bicarbonate and anions in both sexes, and worse in females. This likely has implications for the electrophysiological properties of excitable membranes. It is consistent with the reported impairment of potassium-chloride exchangers in opioid dependence. Explication of the mechanisms responsible must await further studies.

Exploring the Complex Dynamics of an Ion Channel Voltage Sensor Domain via Computation

Voltage-gated ion channels are ubiquitous proteins that orchestrate electrical signaling across excitable membranes. Key to their function is activation of the voltage sensor domain (VSD), a transmembrane four alpha-helix bundle that triggers channel opening. Modeling of currents from electrophysiology experiments yields a set of kinetic parameters for a given channel, but no direct molecular insight. Here we use molecular dynamics (MD) simulations to determine the free energy landscape of VSD activation and to, ultimately, predict the time evolution of the resulting gating currents. Our study provides the long-sought-for bridge between electrophysiology and microscopic molecular dynamics and confirms, as already suggested on the basis of experiments, that rate-limiting barriers play a critical role in activation kinetics.