75 research outputs found
Theoretical predictions of gating behavior for mutants of Shaker-type Kv channels from inter-domain energetics
No full textA multiscale physical model of Shaker-type Kv channels is used to span from atomic-scale interactions to macroscopic experimental measures such as charge/voltage (QV) and conductance/voltage (GV) relations. The model [1] comprises the experimentally well-characterized voltage sensor (VS) domains described by four replications of an independent continuum electrostatic model under voltage clamp conditions [2, 3] and a hydrophobic gate controlling the flow of ions by a vapor lock mechanism [4], connected by a simple coupling principle derived from known experimental results and trial-and-error. The total Hamiltonian of the system is calculated from the computed configurational energy for each components as a function of applied voltage, VS positions andg ate radius, allowing us to produce statistical-mechanical expectation values for macroscopic laboratory observables over the full range of physiological membrane potentials (|V| ≤ 100 mV, in 1 mV steps). The Shaker QV and GV relations seen in Seoh et al. [5] are predicted by this model. With this approach, functional energetic relations can be decomposed in terms of physical components, and thus the effects of modifications in those elements can be quantified. We find that the total work required to operate the gate is an order of magnitude larger than the work available to the VS, and that the the experimentally observed bistable gating is due to the VS slide-and-interlock behavior. The same model was systematically applied to VS charge mutants (Seoh et al. [5]). The QV and GV relations can be qualitatively predicted and the associated effects on functional domains determined. Additional features such as surface charges become significant for the pathological cases. Our engineering approach clearly elucidates that both normal function and mutant changes are electrostatic in nature.[1] Alexander Peyser, Dirk Gillespie, Roland Roth, and Wolfgang Nonner. Domain and inter-domain energetics underlying gating in Shaker-type Kv channels. Accepted: Biophys J,2014. doi:10.1016/j.bpj.2014.08.015.[2] Alexander Peyser and Wolfgang Nonner. Voltage sensing in ion channels: Mesoscale simulations of biological devices. Phys Rev E StatNonlin Soft Matter Phys, 86: 011910, Jul 2012. doi:10.1103/PhysRevE.86.011910.[3] Alexander Peyser and Wolfgang Nonner. The sliding-helix voltage sensor: mesoscale views of a robust structure-function relationship. Eur Biophys J, 41:705–721,2012. doi:10.1007/s00249-012-0847-z.[4] Roland Roth, Dirk Gillespie, Wolfgang Nonner, and Robert E. Eisenberg. Bubbles, gating, and anesthetics in ion channels. Biophys J, 94(11):4282–4298,2008. doi:10.1529/biophysj.107.120493.[5] Sang-Ah Seoh, Daniel Sigg, Diane M. Papazian, and Francisco Bezanilla. Voltage-sensing residues in the S2 and S4 segments of the Shaker K+ channel. Neuron, 16 (6):1159–1167, 1 June1996. doi:10.1016/S0896-6273(00)80142-7.[6] Stephen B. Long, Xiao Tao, Ernest B. Campbell, and Roderick MacKinnon. Atomic structure of a voltage-dependent K+ channel in a lipid membrane-like environment. Nature, 450(7168):376–382,2007. doi:10.1038/nature06265
The transient potassium conductance of the somatic membrane of cultured embryonic rat neurons
No full textThe transient K conductance of rat central neurons was studied under voltage clamp. Currents were recorded through tight-seal pipettes from whole neurons or 3-8 m spheres of excised somatic membrane ('blebs'). Whole cells revealed a tetrodotoxin-sensitive Na current, followed by a K current that passed through a peak and was maintained at 60-90% of the peak during 300 ms. Somatic membrane isolated in the form of blebs also conducted Na and K currents, but the K current was mostly, and often exclusively, transient. This current was blocked by 4-aminopyridine (5 mM), but not affected by tetraethylammonium ion (1 mM).A transient K current was activated by depolarizations greater than 40 mV. Peak conductance increased in proportion to voltage with no indication of saturation up to +80 mV. Ensemble fluctuations suggested that less than 50% of the channels were open at the peak during a +40 mV depolarization. Steady-state inactivation was minimal after conditioning at 100 mV, and was complete at 50 to 30 mV. Recovery from inactivation followed a sigmoidal time course (half time ca. 50 ms at 90 mV, 25\sp\circC).Substitution of external Na by K ion altered activation, but not inactivation. In high K, a given depolarization activated a larger and more rapidly rising conductance that could be saturated. Substitution of 1 mM external Mg by 1 mM Ca, or addition of 0.5 mM Cd, slowed activation.The gating characteristics of the transient K current varied significantly from neuron to neuron. Half times of inactivation, although constant and stable for a given neuron varied from 5 to 65 ms at 25\sp\circC. Activation half-times ranged from 1 to 2 ms (+40 mV). The position on the voltage axis of peak conductance and steady-state inactivation curves varied over 30 mV. The degree of preceding inactivation did not affect the time course of the currents, suggesting channels of a given preparation were uniform in their inactivation properties.Possible kinetic models of the transient K channel gating are discussed. It appears that opening of these channels during activation involves a final reaction step that is weakly voltage dependent, and possibly ion dependent. The variability of the channel's gating properties is discussed in the context of mechanisms. (Abstract shortened with permission of author.)</p
Comparison of groundwater recharge estimation methods for the semi-arid Nyamandhlovu area, Zimbabwe
No full textThe Nyamandhlovu aquifer is the main water resource in the semi-arid Umguza district in Matebeleland North Province in Zimbabwe. The rapid increase in water demand in the city of Bulawayo has prompted the need to quantify the available groundwater resources for sustainable utilization. Groundwater recharge estimation methods and results were compared: chloride mass balance method (19–62 mm/year); water-table fluctuation method (2–50 mm/year); Darcian flownet computations (16–28 mm/year); 14C age dating (22–25 mm/year); and groundwater modeling (11–26 mm/year). The flownet computational and modeling methods provided better estimates for aerial recharge than the other methods. Based on groundwater modeling, a final estimate for recharge (from precipitation) on the order of 15–20 mm/year is believed to be realistic, assuming that part of the recharge water transpires from the water table by deep-rooted vegetation. This recharge estimate (2.7–3.6% of the annual precipitation of 555 mm/year) compares well with the results of other researchers. The advantages/disadvantages of each recharge method in terms of ease of application, accuracy, and costs are discussed. The groundwater model was also used to quantify the total recharge of the Nyamandhlovu aquifer system (20?×?106–25?×?106 m3/year). Groundwater abstractions exceeding 17?×?106 m3/year could cause ecological damage, affecting, for instance, the deep-rooted vegetation in the area.WatermanagementCivil Engineering and Geoscience
On the validity of modeling concepts for the simulation of groundwater flow in lowland peat areas – case study at the Zegveld experimental field
No full textCivil Engineering and Geoscience
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The transient potassium conductance of the somatic membrane of cultured embryonic rat neurons
No full textThe transient K conductance of rat central neurons was studied under voltage clamp. Currents were recorded through tight-seal pipettes from whole neurons or 3-8 m spheres of excised somatic membrane ('blebs'). Whole cells revealed a tetrodotoxin-sensitive Na current, followed by a K current that passed through a peak and was maintained at 60-90% of the peak during 300 ms. Somatic membrane isolated in the form of blebs also conducted Na and K currents, but the K current was mostly, and often exclusively, transient. This current was blocked by 4-aminopyridine (5 mM), but not affected by tetraethylammonium ion (1 mM).A transient K current was activated by depolarizations greater than 40 mV. Peak conductance increased in proportion to voltage with no indication of saturation up to +80 mV. Ensemble fluctuations suggested that less than 50% of the channels were open at the peak during a +40 mV depolarization. Steady-state inactivation was minimal after conditioning at 100 mV, and was complete at 50 to 30 mV. Recovery from inactivation followed a sigmoidal time course (half time ca. 50 ms at 90 mV, 25\sp\circC).Substitution of external Na by K ion altered activation, but not inactivation. In high K, a given depolarization activated a larger and more rapidly rising conductance that could be saturated. Substitution of 1 mM external Mg by 1 mM Ca, or addition of 0.5 mM Cd, slowed activation.The gating characteristics of the transient K current varied significantly from neuron to neuron. Half times of inactivation, although constant and stable for a given neuron varied from 5 to 65 ms at 25\sp\circC. Activation half-times ranged from 1 to 2 ms (+40 mV). The position on the voltage axis of peak conductance and steady-state inactivation curves varied over 30 mV. The degree of preceding inactivation did not affect the time course of the currents, suggesting channels of a given preparation were uniform in their inactivation properties.Possible kinetic models of the transient K channel gating are discussed. It appears that opening of these channels during activation involves a final reaction step that is weakly voltage dependent, and possibly ion dependent. The variability of the channel's gating properties is discussed in the context of mechanisms. (Abstract shortened with permission of author.)</p
Comparison of different base flow separation methods in a lowland catchment
No full textAssessment of water resources available in different storages and moving along different pathways in a catchment is important for its optimal use and protection, and also for the prediction of floods and low flows. Moreover, understanding of the runoff generation processes is essential for assessing the impacts of climate and land use changes on the hydrological response of a catchment. Many methods for base flow separation exist, but hardly one focuses on the specific behaviour of temperate lowland areas. This paper presents the results of a base flow separation study carried out in a lowland area in the Netherlands. In this study, field observations of precipitation, groundwater and surface water levels and discharges, together with tracer analysis are used to understand the runoff generation processes in the catchment. Several tracer and non-tracer based base flow separation methods were applied to the discharge time series, and their results are compared.WatermanagementCivil Engineering and Geoscience
Discrete conductance levels in calcium channel models : multiband calcium selective conduction
No full textBrownian dynamics were simulated for the simple model of calcium channels introduced by Nonner and Eisenberg, computing electric forces from all charges. Permanent charge (of acidic side chains) was varied. Substantial conduction was found only at certain discrete values of permanent charge. Different con-duction states had different selectivity, one resembling L-type CaV1 and the other RyR channels. We speculate that thermally acti-vated switching between conductance values could produce some types of spon-taneous gating. Below is calcium current J as a function of permanent charge Qf and calcium concentration
Differential Effects of Insulin on Choline Acetyltransferase and Glutamic Acid Decarboxylase Activities in Neuron‐Rich Striatal Cultures
No full textWe studied the effects of insulin, nerve growth factor (NGF), and tetrodotoxin (TTX) on cellular metabolism and the activity of glutamic acid decarboxylase (GAD) and choline acetyltransferase (ChAT) in neuron-rich cultures prepared from embryonic day 15 rat striatum. Insulin (5 micrograms/ml) increased glucose utilization, protein synthesis, and GAD activity in cultures plated over a range of cell densities (2,800-8,400 cells/mm2). TTX reduced GAD activity; NGF had no effect on GAD activity. Insulin treatment reversibly reduced ChAT activity in cultures plated at densities of greater than 4,000 cells/mm2, and the extent of this reduction increased with increasing cell density. The number of acetylcholinesterase-positive neurons was not reduced by insulin, suggesting that insulin acts by down-regulating ChAT rather than by killing cholinergic neurons. Insulin-like growth factor-1 (IGF-1) reduced ChAT activity at concentrations 10-fold lower than insulin, suggesting that insulin's effect on ChAT may involve the IGF-1 receptor. NGF increased ChAT activity; TTX had no effect on ChAT activity. These results suggest that striatal cholinergic and GABAergic neurons are subject to differential trophic control
SRPT Is 1.86-competitive for Completion Time Scheduling
No full textWe consider the classical problem of scheduling preemptible jobs, that ar-rive over time, on identical parallel machines. The goal is to minimize the total completion time of the jobs. In standard scheduling notation of Graham et al. [5], this problem is denoted P | rj,pmtn | j cj. A pop-ular algorithm called SRPT, which always schedules the unfinished jobs with shortest remaining processing time, is known to be 2-competitive, see Phillips et al. [12, 13]. This is also the best known competitive ratio for any online algorithm. However, it is conjectured that the competitive ra-tio of SRPT is significantly less than 2. Even breaking the barrier of 2 is considered a significant step towards the final answer of this classical online problem. We improve on this open problem by showing that SRPT is 1.86-competitive. This result is obtained using the following method, which might be of general interest: We define two dependent random variables that sum up to the difference between the cost of an SRPT schedule and the cost of an optimal schedule. Then we bound the sum of the expected values of these random variables with respect to the cost of the optimal schedule, yielding the claimed competitiveness. Furthermore, we show a lower bound of 21/19 for SRPT, improving on the previously best known 12/11 due to Lu et al. [10]
Physical Chemistry of Excitable Biomembranes
No full textNeumann E, Bernhardt J. Physical Chemistry of Excitable Biomembranes. Annual Review of Biochemistry. 1977;46(1):117-141
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